© 2019. Published by The Company of Biologists Ltd | Development (2019) 146, dev156000. doi:10.1242/dev.
156000
REVIEW
The origins and non-canonical functions of macrophages
in development and regeneration
Marine Theret1,2, Remi Mounier3 and Fabio Rossi1,2,*
ABSTRACT
The discovery of new non-canonical (i.e. non-innate immune) functions
of macrophages has been a recurring theme over the past 20 years.
Indeed, it has emerged that macrophages can influence the
development, homeostasis, maintenance and regeneration of many
tissues and organs, including skeletal muscle, cardiac muscle, the
brain and the liver, in part by acting directly on tissue-resident stem
cells. In addition, macrophages play crucial roles in diseases such as
obesity-associated diabetes or cancers. Increased knowledge of their
regulatory roles within each tissue will therefore help us to better
understand the full extent of their functions and could highlight
new mechanisms modulating disease pathogenesis. In this Review,
we discuss recent studies that have elucidated the developmental
origins of various macrophage populations and summarize our
knowledge of the non-canonical functions of macrophages in
development, regeneration and tissue repair.
KEY WORDS: Macrophage, Homeostasis, Stem cells
Introduction
The immune functions of macrophages (MPs) were first highlighted
by Elie Metchnikoff, who was awarded the Nobel Prize in Physiology
or Medicine in 1908. He developed the now commonly accepted
theory that phagocytic cells, such as MPs, monocytes (MOs) and
neutrophils, fight against pathogens (reviewed by Cavaillon, 2011).
Subsequently, during the 20th century, a lineage relationship between
circulating blood MOs and the MPs found in inflamed tissues was
discovered, first in 1930 in the amphibian larvae model and later in
1939 for mammals (Cavaillon, 2011). This was soon followed by
myriad studies of macrophage activation and functions in
inflammation.
In its most reductionist definition, inflammation is described as a
process that is triggered in response to viral or bacterial infections.
However, it is now commonly accepted that sterile inflammation
(non-pathogen-induced inflammation) also occurs in multiple
settings, including during development and in afflictions such as
autoimmune disease and cancers, and even in aging (Jackaman et al.,
2017). Moreover, it is clear that any form of tissue damage invariably
triggers sterile inflammation, influencing outcomes spanning from
functional restoration to fibrosis depending on the efficiency of the
regenerative process. Importantly, MPs are now thought to play key
roles in modulating such processes, and recently developed molecular
1
Department of Medical Genetics, The Biomedical Research Centre, University of
British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
2
Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences
Mall, Vancouver, BC V6T 1Z3, Canada. 3Institut Neuromyogène, CNRS UMR 5310,
INSERM U1217, Université de Lyon, 69008 Lyon, France.
*Author for correspondence (fabio@brc.ubc.ca)
M.T., 0000-0002-8059-8756; R.M., 0000-0003-3464-3322; F.R., 0000-0002-
0368-2620
tools have provided strong evidence for their ability to execute tissue-
specific tasks beyond the response to pathogens (Davies et al., 2013).
In this Review, we describe some of these non-canonical and organ-
specific functions of MPs. We begin by providing an overview of the
populations of MPs that exist and discussing their developmental
origins. We then highlight how such MPs function in the context of
tissue development, homeostasis and repair.
Macrophage origins during development and adulthood
In summary, at least three developmentally distinct types of MPs
exist in the body: yolk sac (YS)-derived tissue-resident MPs, fetal
liver-derived tissue-resident MPs, and infiltrating bone marrow-
derived MPs. All of these MPs emerge at different points during
development and adulthood (Fig. 1) and play key roles in tissue
development, growth, homeostatic maintenance and remodeling
(reviewed by Epelman et al., 2014b).
The emergence of MPs: from embryonic to adult hematopoiesis
During embryogenesis, MPs are detected in most organs and tissues
including the brain, heart, liver and skeletal muscle. The progeny of
these first tissue-resident MPs persist for the life of the organism.
The precise ontogeny of embryonic MPs is still debated, but it has
been elegantly demonstrated that at least one subset arises before the
appearance of the first multipotent hematopoietic stem cells (HSCs)
(Ginhoux and Guilliams, 2016). For example, during early
embryogenesis in mice, ‘primitive’ hematopoiesis takes place in
the extra-embryonic YS [embryonic day (E)6.5 to E11] and gives
rise to MPs (Fig. 1), which are the only ‘white’ hematopoietic cells
found in the embryo at this time point. Later, from E8.5 to E12,
immature HSCs emerge from the aorta-gonad-mesonephros (AGM)
and give rise to other early immune lineages (which do not include
lymphoid cells) (Orkin and Zon, 2008). These immature HSCs
eventually colonize the fetal liver (between E10-P1). Soon after
birth (E19-P1), fetal liver HSCs migrate to the bone marrow and
give rise to mature HSCs that are capable of generating all blood
lineages, including MPs, in a process called ‘definitive’
hematopoiesis (E19-P1) (Fig. 1) (Palis and Yoder, 2001; Orkin
and Zon, 2008). In addition to the fetal liver, the placenta has been
revealed as a site of active hematopoiesis (between E10-E13)
(Dzierzak and Robin, 2010). At each of these stages, MP precursors
are generated and seed a specific subset of organs, often establishing
local lineages that will last the organism’s lifetime.
DEVELOPMENT
During adulthood, MOs/MPs originate in the bone marrow via
a differentiation cascade that comprises multiple cellular
intermediates. According to a classical model, HSCs give rise to
common myeloid progenitors (CMPs) that generate additional
progenitors that are further restricted in their developmental
potential, i.e. granulocyte-monocyte progenitors (GMPs) and
megakaryocyte-erythrocyte progenitors (MEPs) (Fig. 2A).
However, this classical model has been challenged for years, and
alternative models in which all other myeloid cells (neutrophils,
1
REVIEW
Yolk Sac AGM Liver
E6.5 E8.5 E10 E11 E12 E19
Heart-resident MPs
Microglia Langerhans cells Skeletal muscle-resident MPs
Kupffer cells Dermis-resident MPs
Alveolar MPs Gut-resident MPs
eosinophils, mast cells), in addition to MOs/MPs, also come from
GMPs has been suggested (Kierdorf et al., 2015; Ginhoux and
Guilliams, 2016; Yamamoto et al., 2018) (Fig. 2A). Even today, the
debate is not settled. For example, based on single cell RNA
sequencing, Drissen and colleagues recently proposed that mast
cells, basophils and eosinophils arise from a different, earlier
progenitor (Gata1+) than do neutrophils and MOs (Flt3+) (Drissen
et al., 2016; Sarrazin and Sieweke, 2016) (Fig. 2B). In parallel, the
existence of MEPs has been questioned by reports demonstrating
that erythrocytes and megakaryocytes can directly derive from
HSCs, both during fetal development and during adulthood
(Adolfsson et al., 2005; Notta et al., 2016) (Fig. 2B).
In conclusion, our understanding of the hematopoietic lineage is
evolving fast, thanks to rapid progress in single cell-based
techniques, and has highlighted that the MP lineage can arise at
multiple points during development and adulthood (Figs 1 and 2).
The cellular origins and maintenance of tissue-resident macrophages
Tissue-resident MPs are the most abundant immune cell present in
most tissues, yet at resting state they are still rare compared with
parenchymal cells. In 1968, Van Furth and Cohn proposed that
tissue-resident MPs originate from circulating blood MOs (van
Furth and Cohn, 1968). This hypothesis has been accepted for many
years without more thorough investigation. More recently, however,
the development of new murine models allowing the specific
labeling of MO/MP populations in vivo (Box 1) has allowed
researchers to explore the ontogeny and roles of the different subsets
of MOs and MPs found in tissues.
For example, mice that express GFP from the CX3CR1 locus,
which encodes the receptor for the chemokine CX3CL1, have
provided a tool for following MOs and MPs within blood and
tissues (Jung et al., 2000; Geissmann et al., 2003). The subsequent
development of CX3CR1-creER mice has allowed lineage tracing
studies, confirming that at least a subset of tissue-resident MPs is
established during embryogenesis and self-renews in peripheral
tissues during adulthood (Yona et al., 2013; Salter and Beggs,
2014). Furthermore, by using CCR2-KO mice, in which MOs lose
their responsiveness to CCL2 and therefore fail to infiltrate tissues,
Hashimoto and colleagues showed that blood-derived MPs are not
Development (2019) 146, dev156000. doi:10.1242/dev.156000
Bone marrow Fig. 1. Waves of hematopoiesis and MP
emergence. From E6.5 to E11, primitive
hematopoiesis takes place in the YS and tissue-
resident MPs such as microglia and Langerhans cells
appear in their respective tissues. Later, from E8.5 to
E12, immature HSCs appear from the AGM and give
rise to Kupffer cells and alveolar MPs. From E10 to
E19/P1 (birth), the fetal liver starts generating all
immune cells, and tissue-resident MPs within the
cardiac system, skeletal muscle, dermis and gut
P1 colonize their respective tissues. Soon after birth,
hematopoiesis shifts to the bone marrow and gives rise
to circulating blood monocytes that replace a
percentage of tissue-resident macrophages over time.
required for maintaining lung-, spleen- and peritoneum-resident MP
homeostasis (Hashimoto et al., 2013). Other lineage tracing models,
such as Kit-Mer-Cre-Mer, Tek-Mer-Cre-Mer, Csfr1-Mer-Cre-Mer or
Runx1-Mer-Cre-Mer, specifically target YS-derived hematopoietic
cells. In these models, activation of Cre recombinase at E7 targets
the YS hematopoietic system but at E8.5 and beyond targets the
‘definitive’ hematopoietic system. This allowed independent
validation of the existence of two waves of erythro-myeloid
progenitors contributing to tissue-resident MOs (Ginhoux et al.,
2010; Hoeffel et al., 2012; Hoeffel and Ginhoux, 2015).
Additional studies have clarified that progenitors derived from
the YS give rise to MPs in the brain (microglia), and to a fraction of
tissue-resident MPs in other organs such as the heart, lung (alveolar
MPs), liver (Kupffer cells), spleen, bone (osteoclasts) and skin
(Langerhans cells) (Merad et al., 2002; Guilliams et al., 2013;
Hashimoto et al., 2013; Jakubzick et al., 2013; Epelman et al.,
2014b; Molawi et al., 2014; Gomez Perdiguero et al., 2015). Thus,
with the exclusion of microglia, tissue-resident MP populations in
other tissues comprise cells of multiple developmental origins
(Fig. 1), at least some of which are maintained locally from early
development onwards.
A correct number of tissue-resident MPs needs to be maintained
during adulthood. Although the self-renewal of tissue-resident MPs
is complex, tissue specific and not yet fully understood, we know
that the long-term maintenance of tissue-resident MPs is essential
(Aziz et al., 2009; Jenkins and Hume, 2014). Indeed, the disruption
of MP numbers or their inflammatory state can lead to severe defects
in organ function during life, leading to early aging (Linehan and
Fitzgerald, 2015).
During adult life, a percentage of tissue-resident MPs, variable
DEVELOPMENT
from tissue to tissue, is continuously renewed by blood-derived
MPs. However, whether these cells should be considered as ‘tissue-
resident’ MPs is a matter for debate. In addition, this process does
not occur to the same extent in all tissues. For example, microglia
are capable of self-renewal in their tissue of residence and
are completely independent of definitive hematopoietic
progenitors for their maintenance, and circulating bone marrow-
derived myelomonocytic cells only enter the CNS in the context of
disease (Ajami et al., 2007).
2
REVIEW Development (2019) 146, dev156000. doi:10.1242/dev.156000

Fig. 2. Models of adult hematopoiesis.

A Original model LT-HSC
(A) Original model of adult hematopoiesis. In this
simple model, basophils, eosinophils, neutrophils
and monocytes derive from a common progenitor
called a granulocyte-monocyte progenitor (GMP).
ST-HSC (B) Revised model of adult hematopoiesis. The
revised version of hematopoiesis adds layers of
CMP LMPP complexity. For example, neutrophils and
monocytes come from an independent Flt3+
MEP
GMP neutrophil-monocyte progenitor (NMP), unlike
CLP basophils and eosinophils, which arise from a
Gata1+ progenitor. In addition, erythrocytes and
megakaryocytes hail from distinct intermediate
progenitors that arise downstream of
NK cell megakaryocyte-erythrocyte progenitors (MEPs),
Basophil i.e. E-MEPs and MK-MEPs. CLP, common
Monocyte lymphoid progenitor; CMP, common myeloid
Platelet progenitor; E-MEP, erythroid-primed MEP; EMP,
Erythrocyte Eosinophil Neutrophil Lymphocyte eosinophil-mast cell progenitor; LMPP, lymphoid-
primed multipotent progenitor; LT-HSC, long-term
hematopoietic stem cell; MK-MEP, megakaryocyte-
primed MEP; NK, natural killer; NMP, neutrophil-
B Revised model monocyte progenitor; ST-HSC, short-term
LT-HSC
hematopoietic stem cell.

ST-HSC

E-MEP pre-MEP Flt3+

Gata1+

CLP

MK-MEP NMP
EMP
NK cell
Erythrocyte

Lymphocyte
Platelet Monocyte
Basophil Eosinophil Neutrophil

Tissue-resident MPs also display distinct molecular
characteristics depending on their tissue of residence, but the links
between them are unclear (Ayata et al., 2018). For example, do
resident MPs in different tissues come from the same type of
progenitor during development, suggesting that their specialization
takes place due to environmental signals present in the target tissue?
Or do specific progenitors exist, with different predispositions for
infiltrating specific organs, suggesting that at least some of the
reported differences are cell autonomous? In this context the
existence of a niche, composed of tissue-specific cells, which could
induce MP specialization has been proposed (Gautier and Yvan-
Charvet, 2014; Guilliams and Scott, 2017). The fate of resident MPs
following catastrophic damage also appears to vary depending on
the tissue. For example, following ablation in the CNS, microglia
are restored from a small number of surviving YS-derived cells
In summary, the ontogeny and behavior of tissue-resident MPs
has started to be unlocked over the past decade, revealing that many
of these cells originate during embryonic development. Although
many questions remain, the combination of single cell-based
technologies and new specific markers for adult tissue-resident cells
should rapidly lead to their answers.
Infiltrating bone marrow-derived MPs
In addition to the tissue-resident MPs discussed above, MPs can arise
from MOs that are present within the blood and that infiltrate into
tissues. Two types of MOs, classified according to their expression of
the marker Ly6C, are found in the circulation in both mice and humans.
Their ratio in the blood is dynamic and changes in response to various
stimuli (e.g. bacterial or virus infection, tissue damage and sterile
inflammation). Ly6C+ MOs originate directly from bone-marrow
progenitors, whereas Ly6C− MOs likely arise from circulating Ly6C+
DEVELOPMENT

without contribution from the bone marrow (Elmore et al., 2014;

Huang et al., 2018). In contrast, YS-derived cells in the heart, which
form a sizable subset of tissue-resident MPs, are replaced by blood-
derived MOs (Epelman et al., 2014b). It is unclear whether these
‘new’ tissue-resident MPs have the same function as the embryo-
derived ones (Blériot et al., 2015; Machiels et al., 2017). For further
consideration about tissue-resident MP ontogeny, fate and self-
renewal, we refer the reader to recent reviews (Sieweke and Allen,
2013; Ginhoux and Guilliams, 2016; Kierdorf and Dionne, 2016).
MOs (Yona et al., 2013). Functionally, these two populations are
different. The Ly6C+ MO subset responds to damage by infiltrating the
tissue and then differentiating into MPs. In contrast, Ly6C− MOs do
not infiltrate tissues, but rather patrol the vascular system to detect and
likely remove damaged endothelial cells within vessels (Geissmann
et al., 2003; Carlin et al., 2013; Jakubzick et al., 2013).
After a long debate on the origins of blood-derived MPs found in
damaged tissue, it is now commonly accepted that infiltrating MPs

3
REVIEW
Box 1. Mouse models for studying MPs
Csf1op/Csf1op: These mice carry a spontaneous null mutation in the
Csf1 gene, leading to loss of circulating MOs and tissue-resident MPs
(but not microglia), with significant effects on the development of many
tissues and organs.
Csf1r−/Csf1−: Deletion of both Csf1 and its receptor Csf1r leads to
severe defects in hematopoiesis and MPs. Most of the phenotypes
observed in these mice are similar to those seen in the Csf1op/Csf1op
model, but these mice lack additional populations such as microglia (Dai
et al., 2002) and thus exhibit a stronger phenotype.
CCR2-KO: This model targets CCR2, which is a receptor expressed by
MOs and involved in their chemotaxis. This model is widely used to
abrogate the infiltration of circulating blood MOs in tissues after damage,
and to analyze MP involvement in this process (Boring et al., 1997). The
CCL2-KO model, in which the ligand for CCR2 is targeted, is a
complementary model (Lu et al., 1998).
CX3CR1-GFP: In this strain, GFP labels all MOs and MPs. This model is
very useful for FACS-based analysis and in situ visualization of MOs and
MPs (Jung et al., 2000; Geissmann et al., 2003).
CX3CR1creER: This model allows long-lived or self-renewing MP subsets
to be specifically labeled (Yona et al., 2013).
CD11b-DTR: In this model, CD11b+ cells undergo apoptosis after
diphtheria toxin injection. This model thus efficiently depletes circulating
CD11b+ cells but not tissue-resident CD11b+ cells. However, CD11b is
also expressed in various leukocytes such as eosinophils and
neutrophils, thus the CD11b-DTR model, like the GM-CSF-KO model
(below) is not specific to MPs.
GM-CSF-KO (Csf2−/−): This model targets GM-CSF, which is secreted
by a variety of cells and stimulates granulocyte and MP differentiation.
Although most GM-CSF-KO mice appear to be superficially healthy, they
exhibit altered hematopoiesis.
PU.1-KO: These mice are deficient for Pu.1, which encodes an ETS family
transcription factor that is exclusively expressed by the hematopoietic
lineage. Pu.1-deficient mice die in the 48 h following birth owing to the
absence of a range of immune cells (McKercher et al., 1996).
(in contrast to tissue-resident MPs) only arise from Ly6C+ MOs
recruited from the bloodstream, and are associated with the
scavenging of damaged tissue components, wound healing and
tissue remodeling (Arnold et al., 2007; Mounier et al., 2013; Juban
et al., 2018).
After tissue injury, MO infiltration is dramatic, and essentially
equivalent in the majority of tissues, with the noticeable exception
of the CNS, in which infiltration following sterile damage is limited
because of the blood-brain barrier (Engelhardt and Ransohoff,
2012). Infiltration involves CCR2, the receptor for the tissue-
damage induced chemoattractant CCL2. CCR2 is highly expressed
in Ly6C+ MOs and is required for them to infiltrate tissues.
Importantly, studies of CCR2-KO mice (Box 1), in which MOs fail
to infiltrate in response to damage, have revealed that blood-derived
MPs are required for the efficient regeneration of many tissues
(Boring et al., 1997).
Functionally, blood-derived MPs are plastic cells that can adopt
different transcriptional programs depending on the cytokines that
are present in the microenvironment, assuming a range of functions
spanning from the promotion of inflammatory and adaptive immune
responses to their inhibition in favor of tissue regeneration (Epelman
et al., 2014b). In sterile damage, these ‘polarization’ states are often
not the result of classical, irreversible binary cell fate decisions but
rather are sequentially acquired according to a well-defined
temporal succession. Early after damage, Ly6C+ MOs enter the
tissue and differentiate into pro-inflammatory MPs (classically
called ‘M1’ MPs, see Box 2). These cells, which are
Ly6C+CCR2+CX3CR1midF4/80 (Adgre1)mid (Table 1), scavenge
Development (2019) 146, dev156000. doi:10.1242/dev.156000
apoptotic debris but also modulate tissue-specific stem cells through
the secretion of multiple factors (Freire-de-Lima et al., 2000; Johann
et al., 2006; Arnold et al., 2007). Next, these MPs transition to a
pro-restorative status (or the ‘M2’ state, see Box 2 and Table 1).
These Ly6C−CCR2−CX3CR1highF4/80high cells are associated
with fibrosis formation, wound healing and tissue regeneration.
Historically, these phenotypes and related polarization states have
been defined mostly based on in vitro results. It is therefore unclear
how similar the cells found in damaged tissues are to the MPs that
are generated in vitro by exposing bone-marrow progenitors to
specific cytokine cocktails (Martinez et al., 2008). For this reason,
and also reflecting a recent rejection of the M1/M2 terminology in
the literature (Varga et al., 2013; Varga et al., 2016a,b), pro-
inflammatory M1 MPs will be referred to hereafter as Ly6C+ MPs,
and pro-restorative M2 MPs will be called Ly6C− MPs (see Box 2).
The function of tissue-resident macrophages in organ
development and homeostasis
Although significant differences are maintained between tissue-
resident MPs and MO-derived infiltrating MPs, these are not
obvious, and phenotypically the cells are very similar. This raises
questions about the overlap in biological functions between these
two populations (reviewed by Epelman et al., 2014b). As an
example, in the bone marrow itself, MPs are required for correct
hematopoiesis. Their depletion affects the HSC niche and induces
HSC mobilization in the blood (Winkler et al., 2010; Gustafsson and
Welsh, 2016). Moreover, MPs are also required to be in direct
contact with erythroblasts in the bone marrow for proper
erythropoiesis (Chow et al., 2013). These two examples
demonstrate that tissue-resident MPs are crucial even for their
own homeostasis. However, animals congenitally deficient for
tissue-resident MPs have reduced survival, making the study of MP
function during embryogenesis or postnatal growth a difficult task.
For example, mice carrying a spontaneous mutation in Csf1 (op/op
mice), a factor that is essential for the maintenance of mature MPs,
present many abnormalities (Dai et al., 2002). This is owing to a
lack of osteoclasts, which are multinucleated cells that are formed by
fusion of MPs with each other and are required for bone resorption.
As a result, bone deposition is excessive in these mice, cavities
for bone marrow are not formed and hematopoiesis is deeply
altered (Dai et al., 2002), making it hard to distinguish direct and
indirect effects of the lack of MPs. Likewise, deletion of the
Box 2. The M1-M2 paradigm for macrophages
The M1 and M2 terminology was initially used to parallel the Th1 and Th2
nomenclature used to describe T cells (Mills et al., 2000). Indeed, Th1-
skewed mice (C56BL/6) are more prone to produce M1 macrophages,
whereas Th2-skewed mice (BALB/c) are more biased towards M2
macrophage production (Mills et al., 2000; Ley, 2017). However, these
phenotypes were defined based on in vitro results using INFγ (M1), IL4
(M2a), IL10 (M2c) and opsonized bacteria/lipopolysaccharide (M2b) in
different combinations (Martinez et al., 2008). Although this
nomenclature has been helpful, and is still used because of its
DEVELOPMENT
simplicity, it is unclear how similar the cells found in vivo during sterile
damage are to the MPs generated in vitro starting from bone-marrow
progenitors. In this Review, we therefore have opted to use a more
descriptive nomenclature for MPs based on Ly6C expression, i.e. Ly6C+/
Ly6C−. We understand that this terminology is still not perfect, as more
than two ‘flavors’ of MPs exist in vivo. However, Ly6C is still the main
marker used to differentiate the wide categories of inflammatory and
restorative MPs and thus, we believe, is one of the best ways to describe
them.
4
REVIEW Development (2019) 146, dev156000. doi:10.1242/dev.156000

Table 1. MO and MP types and features

Localization Name Phenotype Characteristics
+ + + low low low
Blood Ly6C MO Ly6C CCR2 CX3CR1 F4/80 CD11b Infiltrate tissues when required.
Ly6C− MO Ly6C−CCR2−CX3CR1hiF4/80lowCD11blow Patrol the vascular system.
Resting state tissue Embryonic-derived resident MPs Ly6C−CCR2−F4/80hiCD11blow Independent self-renewal.
Bone marrow-derived resident MPs Ly6C−CCR2−F4/80lowCD11bhigh Continuous self-renewal by circulating MOs.
Exist in all tissues except CNS.
Damaged tissue Infiltrating MPs Ly6C+CCR2+CX3CR1lowF4/80lowCD11blow Associated with early phase of sterile inflammation.
Ly6C− MPs Ly6C−CCR2−CX3CR1hiF4/80hiCD11bhi Come from Ly6C+ MPs. Associated with tissue
remodeling.

hematopoietic-specific transcription factor PU.1 (Spi1) causes
lethality in the late embryo or soon after birth. However, by using
a conditional LysM-Cre PU.1 floxed model, it has been demonstrated
that PU.1 is dispensable for HSC development, allowing the
community to investigate hematopoiesis more thoroughly
(McKercher et al., 1996; DeKoter et al., 1998; Dakic et al., 2005).
Similarly, other conditional knockout mouse models (see Box 1) have
aided the study of tissue-resident MPs, revealing how these cells arise
and are maintained, and highlighting organ-specific roles for these
cells during embryogenesis and early development.
Central nervous systems
Microglia, first described in 1932 (del Rio-Hortega, 1932), are the
resident MPs of the CNS. Microglia are phenotypically identical to
other MPs and share the ability to respond to damage and to
phagocyte cell debris. However, as mentioned above, microglia
have distinct developmental origins: although the timing of their
colonization of the brain is still debated, and is likely to happen at
multiple stages of embryonic life, it is now accepted that microglia
derive mainly from the YS at E8.5-E9 (Alliot et al., 1999; Herbomel
et al., 2001; Ajami et al., 2007; Chan et al., 2007; Ginhoux et al.,
2010; Hashimoto et al., 2013; Salter and Beggs, 2014), before the
origins of the first HSCs and of most adult MPs. Interestingly,
microglia formation is independent of the CSF1/CSF1R axis, but
rather depends on IL34, an alternative ligand for CSF1R (Erblich
et al., 2011; Schulz et al., 2012).
Microglia have important functions during development and adult
life (reviewed in detail by Hammond et al., 2018). As an example, a
lack of microglia in Csf1r−/− mice results in functional deficiencies,
for example in olfaction processing, pointing to a requirement for
these cells during development (Erblich et al., 2011). Indeed, the
number of microglia increases significantly during brain
development, owing to both local proliferation and additional
waves of infiltration (Ginhoux et al., 2010; Erblich et al., 2011). In
addition to playing a role in embryonic and fetal brain development,
microglia are required for normal postnatal development, likely by
modulating interneuronal connections through synaptic pruning
(Graeber and Streit, 2010; Tremblay et al., 2010; Paolicelli et al.,
2011; Fig. 3). This phenomenon is thought to be modulated by
CX3CR1, which is expressed at high levels in microglia. Indeed
CX3CR1-KO animals have a higher number of unconnected
synapses, which is reminiscent of the immature brain and similar to
what can be seen in neurodevelopmental disorders (Graeber and
Streit, 2010; Tremblay et al., 2010; Paolicelli et al., 2011). Moreover,
microglia are able to recognize CD47, which appears to modulate
pruning of neuronal projections (Lehrman et al., 2018; Fig. 3). CD47-
KO mice exhibit increased engulfment of neurons by microglia,
resulting in a decrease in synaptic connections (Lehrman et al., 2018).
Interestingly, the phagocytic activity of microglia is different
depending on their location in the CNS, and depends on epigenetic
changes likely acquired locally (Ayata et al., 2018).
Microglia are also involved in angiogenesis and vessel sprouting
during brain development, acting via the secretion of VEGF (Fig. 3).
This well characterized pro-angiogenic function is shared with other
non-CNS resident MPs, and represents an important pro-cancer
function of tumor-associated MPs (TAMs) (Fantin et al., 2010).
Finally, by analogy with other tissue-resident MPs, microglia are
thought to acquire different functions depending on the local
microenvironment, a process often called polarization. Such
proposed functions range from inflammatory roles, involving the
release of reactive oxygen species (ROS), nitric oxide (NO) or
TNFα, to pro-neurogenic roles. It has also been proposed that, in

Neuron pruning Fig. 3. The functions of microglia. Microglia are YS-

(CX3CR1/CX3CL1) derived tissue-resident MPs that are able to self-renew
throughout adulthood. They actively participate in neuron
Microglia and synapse pruning activity via CX3CR1/CX3CL1 and
CD42 recognition, and in angiogenesis via the secretion of
VEGF during brain development.

Self-renewal
DEVELOPMENT

Vessel sprouting
Synapse pruning (VEGF)
(CD47 recognition)

5
REVIEW
some cases, microglia activation can have a direct neurotoxic effect
(Hellwig et al., 2013). However, the ability of microglia to polarize,
and in particular to polarize to functional states that resemble those
described for MPs in other tissues, is still controversial and based
more on analogy than solid data (Wang et al., 2016).
The cardiovascular system
Tissue-resident MPs in the heart comprise a mixture of cells from
both YS and fetal liver origins (Epelman et al., 2014b). The self-
renewal capacity of these cardiac-resident MPs is unclear and
appears to depend on their anatomical location. Indeed, whereas
some publications report a slow but progressive replacement of
heart-resident MPs by blood-derived MPs with age (Epelman et al.,
2014a; Molawi et al., 2014), others suggest that less than 1% of the
MPs localized in the atrioventricular bundle are replaced (Hulsmans
et al., 2017) (Fig. 4). More recently, it has been demonstrated that
cardiac TIMD4+ MPs are self-renewing with little input from
infiltrating MPs, whereas cardiac TIMD4− MPs are almost fully
replaced by infiltrating MPs (Dick et al., 2019). Whether cardiac
MPs are required during normal development is still unclear. In
contrast to the adult heart, the neonatal heart is able to fully
regenerate, and the depletion of circulating MOs (using clodronate
liposomes) blocks this regenerative capacity (Porrello et al., 2011;
Aurora et al., 2014). This could be because of the absence of
angiogenesis in MP-depleted mice (Aurora et al., 2014). Although
the specific molecular mechanism underlying this observation is not
known, the authors’ suggestion that a lack of MP-derived VEGF may
be crucial appears to be reasonable (Fig. 4). This function matches
the pro-angiogenic function of microglia described above and, by
analogy, also suggests that cardiac MPs are required for the
establishment of a full blood coronary tree during development
(Fantin et al., 2010). Lastly, it has been described that, at resting state,
heart-resident MPs are particularly abundant in the atrioventricular
node, leading to the proposal that they actively communicate with
cardiomyocytes via GAP junctions to regulate cardiac rhythm
(Hulsmans et al., 2017) (Fig. 4), again demonstrating the
importance of tissue-resident MPs.
The skin
The skin is composed of three layers: the epidermis, which directly
faces the external environment, the dermis, which contains hair
AV node-resident MPs
(TIMD4+)
Self-
renewal
Maintain electrical
contraction
(GAP junctions)
Angiogenesis
(VEGF)
Ly6C+ MOs Replenishment
Blood
Heart-resident MPs
(TIMD4−)
Development (2019) 146, dev156000. doi:10.1242/dev.156000
follicles, and the hypodermis, which contains sweat glands, fat and
blood vessels. Various populations of MPs and dendritic cells are
known to be present in the skin but, owing to their phenotypic
overlap, the distinction between them is ambiguous (Henri et al.,
2010; Tamoutounour et al., 2013). Aside from dendritic cells, at least
two types of tissue-resident MPs are present in the skin: Langerhans
cells are mainly present in the epidermis, whereas cutaneous (or
dermal) MPs are more present in the dermis (Di Meglio et al., 2011;
Tamoutounour et al., 2013; Mojumdar et al., 2014). Of note,
Langerhans cells share properties with both MPs and dendritic cells
(e.g. self-renewal and T cell stimulation), making them an
unclassified cell type (i.e. neither MP nor dendritic cell) (Doebel
et al., 2017). In terms of their developmental origins, both
Langerhans cells and cutaneous MPs are highly heterogeneous.
Indeed, Langerhans cells are first derived from YS progenitors but are
later gradually replaced by precursors from fetal liver hematopoiesis
(Fig. 1) (Hoeffel et al., 2012). In contrast, cutaneous MPs appear to
originate from the fetal liver and are then gradually replaced by
circulating Ly6C+ MOs (Varol et al., 2009) (Fig. 1). Langerhans cells
are also able to self-renew, but Ly6C+ MOs can be recruited to replace
these cells after damage (Tamoutounour et al., 2013).
Until after birth, tissue-resident MPs (both Langerhans cells and
cutaneous MPs) are the only immune cells to appear in the skin
(Tamoutounour et al., 2013). So far, the function of tissue-resident
MPs during development of the skin is unknown, however we
hypothesize that they are required for extracellular matrix formation
and/or deposition and skin layer differentiation. The number of
these tissue-resident MPs in the skin also changes during normal
hair cycles, suggesting roles for them during hair follicle
development. For example, the number of Langerhans cells and
cutaneous MPs increases in anagen (the active hair growth phase)
and decreases in telogen (the resting phase), because of MP
apoptosis (Osaka et al., 2007; Wang et al., 2017). Concomitantly, an
increase in Wnts expressed by MPs is found locally, activating
epithelial cells to initiate the anagen phase (Paus, 1998; Castellana
et al., 2014) and suggesting that MPs modulate the activity of hair
follicle stem cells. Consistent with this notion, it has been shown
that Ly6C− MPs secrete TGFβ1 to activate follicular stem cells, and
thus hair regrowth, in the context of wound healing (Rahmani et al.,
2018). Interestingly, this phenomenon is dependent on CX3CR1
but not CCR2 (Rahmani et al., 2018), suggesting it may not involve
Fig. 4. The regulation and function of tissue-resident MPs in
the heart. MPs present in the atrioventricular (AV) node of the
heart autonomously self-renew and actively participate in the
establishment of cardiac rhythm, acting via GAP junctions. By
contrast, tissue-resident macrophages in the myocardium are
replenished via circulating MOs and facilitate angiogenesis via
the secretion of VEGF.
DEVELOPMENT
6
REVIEW
blood-derived, infiltrating cells. In addition, MPs can modulate hair
cycle and hair growth after plucking via the secretion of TNFα
(Chen et al., 2015).
The spleen and liver
Beyond their important functions in immunity, tissue-resident MPs
in the spleen play crucial roles related to the spleen’s function as the
filter of the bloodstream (Fig. 5). Thus, it is perhaps not surprising
that various subsets of these cells exist, segregated in the different
functional areas of this organ. Splenic-resident MPs originate from
the fetal liver, are Spi1 (PU.1-related transcription factor)-
dependent and self-renew mostly independently of blood-derived
cells (Kohyama et al., 2009; Hashimoto et al., 2013; Yona et al.,
2013). Tissue-resident MPs within the red-pulp region of the spleen
are CD11b (Itgam)low, F4/80+ and CD206 (Mrc1)+ and have
important functions in iron processing connected with their main
function: the clearance of damaged red blood cells (Kohyama et al.,
2009). In contrast, MPs in the white-pulp region express different
markers (e.g. CD68 and MERTK) and mainly phagocytose
lymphocytes (Kohyama et al., 2009). Defects in the function of
these white-pulp MPs lead to B cell accumulation and auto antibody
development, providing a link between their scavenger and immune
roles (Khan et al., 2013).
The liver contains a specialized population of resident MPs called
Kupffer cells, named after Karl Wilhelm von Kupffer who
discovered them in 1876 (von Kupffer, 1876). Until recently, it
was commonly accepted that, between E10.5 and E12, AGM-
derived HSCs give rise to fetal liver MOs, which later differentiate
into Kupffer cells (Gomez Perdiguero et al., 2015). However, this
model was recently disputed. Indeed, it was shown that YS-derived
erythro-myeloid progenitors are also able to generate a common
circulating precursor, which colonizes the embryo from E9.5 and
directly gives rise to Kupffer cells in a CX3CR1-dependent way
Liver
CCL2/CCL3/Csf1
Ly6C+ MPs
Ly6C+ MOs
(iron charged
from spleen)
Fe+
Fe+
Fe+
Kupffer Fe+
cells
Ly6C− MOs
Fig. 5. The functions of tissue-resident MPs in the liver and spleen. In the spleen, circulating Ly6C+ MOs and tissue-resident MPs (marked by CD206 or
CD68/MERTK expression) phagocytose dead erythrocytes and lymphocytes. Iron-charged Ly6C+ MOs then migrate to the liver, guided by the secretion
of CCL2, CCL3 and Csf1 from Kupffer cells, and locally liberate the iron for hepatocytes to take up. In the liver, Kupffer cells continuously phagocytose dead cells
and debris (not shown) in order to protect the liver against pathogenicity.
Development (2019) 146, dev156000. doi:10.1242/dev.156000
(Schulz et al., 2012; Mass et al., 2016). After liver colonization, a
distinct transcriptional program (i.e. different to that in YS-derived
cells) is activated, specifically involving the transcription factor
inhibitor of DNA binding 3 (ID3) and leading to the development of
Kupffer cells that are endowed with self-renewal activity (Mass
et al., 2016).
One important non-immune function of Kupffer cells is the
modulation of metabolism in hepatocytes via PPARγ, preventing the
pathogenic accumulation of lipids and thus hepatic steatosis
(Desvergne, 2008; Kang et al., 2008; Odegaard et al., 2008). After
injury, the main function of Kupffer cells is to clear dead cells and
pathogens in order to protect the liver (Nguyen-Lefebvre and
Horuzsko, 2015). Following acute damage (e.g. carbon tetrachloride
injection or bile duct ligation), Kupffer cells (CD11blowF4/80+) are
activated by damage-associated molecular patterns (DAMPs),
upregulate Ly6C, an event that may be indicative of activation
rather than polarization into M1, and contribute to the attraction of
circulating MOs (by secretion of CX3CL1, CCL2 and CCL5) and
other cells such as neutrophils, basophils or natural killer cells (via
CXCL16) (Nguyen-Lefebvre and Horuzsko, 2015; Wynn and
Vannella, 2016) (Fig. 5). Basophils are also of importance for liver
repair, as they are a source of IL4, a pro-proliferative cytokine for
hepatocytes (Blériot et al., 2015). Thus, appropriate coordination
between resident Kupffer cells and cells infiltrating from the
bloodstream is required for damage resolution and maintenance of
liver function.
The role of infiltrating blood-derived macrophages in tissue
homeostasis and repair
After completion of postnatal growth, organs and tissues need to
maintain homeostasis for a prolonged period of time to preserve
function and integrity. The involvement of blood-derived MPs in
organ and tissue homeostasis is paramount. A detailed discussion of
Blood Spleen
Ly6C+ MOs Phagocytosis
Fe+
Fe+
Fe+
Dead Fe+
erythrocytes
Tissue-resident MPs
(CD206)
Dead
lymphocytes
DEVELOPMENT
Phagocytosis
Tissue-resident MPs
(CD68/MERTK)
7
REVIEW Development (2019) 146, dev156000. doi:10.1242/dev.156000

the specific roles of these MPs in every tissue is beyond the scope of
this review. We therefore focus below on the roles of blood-derived
MPs in the homeostasis, as well as the regeneration, of four well-
studied tissues: skeletal muscle, cardiac muscle, the liver and skin
(Fig. 6).
Skeletal muscle regeneration
Despite the fact that skeletal muscle was one of the first tissues in
which the crucial roles played by MPs in damage-induced
regeneration were revealed, a developmental role for macrophages
in this tissue has not been investigated. MPs are present within
muscle at steady state and are found in the perimysium (connective
tissue surrounding muscle fascicles) and the epimysium (fascia
surrounding the muscle) (Saclier et al., 2013b). However, a lack of
tools to discriminate tissue-resident versus infiltrating MPs in
skeletal muscle has made it difficult to ascertain the precise role of
tissue-resident MPs in development. In contrast, it is well
established that infiltrating MOs are required for efficient skeletal
muscle regeneration following acute damage (Fig. 6A). Deletion of
CCR2 delays the infiltration of myelomonocytic cells after damage,
causing a strong impairment of skeletal muscle regeneration and the
appearance of diffused fibrosis, demonstrating that these cells are
crucial for efficient healing (Warren et al., 2005). These findings
were validated by depleting CD11b+ cells using the CD11b-DTR
mice model (Box 1; Jung et al., 2000; Arnold et al., 2007).
Early after skeletal muscle damage, Ly6C+ MPs express various
inflammatory markers (see below) but lose Ly6C within 48-72 h
(Arnold et al., 2007; Mounier et al., 2013; Saclier et al., 2013a,b;
Varga et al., 2016a,b). This phenotype switch, often called skewing,
also occurs in multiple other tissues (e.g. heart, liver or kidney) (Sica
et al., 2015) and is regulated at the DNA, RNA and protein levels
throughout the regenerative process (Ruffell et al., 2009; Mounier
et al., 2013; Varga et al., 2016a,b). Soon after infiltration, Ly6C+ MPs
also express molecules such as TNFα (at high levels), IL6 and IL1β.
Beyond their well-known roles as inflammatory mediators, these
factors also act as mitogens, stimulating myogenic cell proliferation
and inhibiting their differentiation/fusion into damaged fibers
(Sonnet et al., 2006; Arnold et al., 2007; Saclier et al., 2013a,b).

A Skeletal muscle B Heart

Skeletal muscle tissue Blood Cardiac tissue Blood

Ly6C+ MP Ly6C+ MP
Myogenic Ly6C+ MO
cell IL6, IL1β,
IL13

TNFα Ly6C+ MO

FAP Promote scar

formation
TGFβ
,
TGFβ, IL10
GDF3 Ly6C− MP

Ly6C− MO
Ly6C− MP Ly6C− MO
FAPs/fibroblasts

Myofiber Replace resident MPs

C Skin D Liver
Liver Blood
Hair follicle stem cell
Langerhans activation and growth TGFβ1 CXCL16 NK and neutrophil
cells recruitment
Kupffer cell
(Ly6C+)
CX3CR1+ Debris
Anagen Telogen clearance
Apoptosis (hair growth) (resting state)

Ly6C+ MO

Cutaneous MPs
PPARγ
Ly6C+
CX3CL1, CCL2, MO recruitment
Lipid CCL5
Infiltration accumulation
Blood
Hepatocyte
DEVELOPMENT

Fig. 6. Tissue-resident and infiltrating MPs act together to orchestrate tissue repair. (A) After damage, Ly6C+ MOs infiltrate skeletal muscle, differentiate into
Ly6C+ MPs and secrete cytokines such as IL6, IL1β, IL13 or TNFα to support myogenic cell proliferation and to ablate excess fibro/adipogenic progenitors
(FAPs, orange cell). Next, these Ly6C+ MPs transition into Ly6C− MPs, which then activate an anabolic program via TGFβ, IL10 or GD3, resulting in differentiation
of myogenic cells and remaining FAPs (green cells). (B) In the heart, circulating MOs infiltrate the tissue following myocardial infarction, differentiate into Ly6C−
MPs and quickly provide trophic support to FAPs in order to promote fibroblast differentiation and scar formation. (C) The number of Langerhans cells and
cutaneous MPs in the skin changes with the hair growth cycle. During anagen (hair growth), the number of resident MPs increases, favoring hair stem cell
expansion through TGFβ. They then decrease in telogen (the resting phase), because of MP apoptosis, and are replenished by circulating Ly6C+ MOs. (D) After
liver damage, Kupffer cells become activated, upregulate Ly6C and secrete CXCL16, CXC3CL1, CCL2/3 and CCL5 to attract natural killer (NK) cells, neutrophils
and Ly6C+ monocytes. These cells then clear the site of damage and block lipid metabolism in hepatocytes to avoid lipid accumulation and pathogenicity.

8
REVIEW
It is conceivable that, in the context of sterile damage, the non-
inflammatory functions of these factors may be prevalent.
Another key function of Ly6C+ MPs, more in line with their
classical role as scavengers, is the removal of debris via their
phagocytic capacities. Phagocytosis also plays a role in triggering
the transition of MPs to a pro-restorative phenotype through the
activation of signaling pathways linked to metabolic control such as
AMP-activated kinase (AMPK) (Mounier et al., 2013). As a result
of skewing, the cytokines secreted by MPs change dramatically:
inflammatory factors such as TNFα are downregulated whereas pro-
regenerative factors such as IL10, IGF1, VEGF, and TGFβ are
produced and stimulate muscle cell survival, differentiation, fusion
and fiber growth (Fig. 6A) (Arnold et al., 2007; Mounier et al.,
2013; Saclier et al., 2013a; Tonkin et al., 2015). More recently, it has
been shown that the transcription factor PPARγ is required for such
pro-restorative effects and, in particular, for secretion of the TGFβ
family member growth differentiation factor 3 (GDF3). Indeed,
suppression of either PPARγ or GDF3 leads to a delay in the
anabolic processes taking place in the late phase of regeneration
(myogenic cell fusion and myofiber growth) (Fig. 6A) (Varga et al.,
2016a,b). Altogether these results demonstrate that the metabolic
and functional states of MPs are highly correlated (Mounier et al.,
2013; Varga et al., 2016a,b).
During the later stages of skeletal muscle regeneration, vessel
remodeling is required to restore muscle function, which also
appears to involve MPs (Zordan et al., 2014; Latroche et al., 2017).
Ly6C− MPs express matrix-remodeling enzymes such as matrix
metallopeptidases (MMP) 2, 13 and 14, and VEGF, and are
therefore good candidates to mediate vessel remodeling (Zordan
et al., 2014). However, the precise roles of Ly6C+ and Ly6C− MPs
or even of tissue-resident MPs in damage-induced angiogenesis
have yet to be addressed in depth.
Ly6C+ MPs also play a role in regulating fibrosis and fibrogenic
differentiation during muscle regeneration. During early regeneration,
stromal progenitors called fibro/adipocytic progenitors (FAPs)
expand dramatically to establish a trophic environment but are then
cleared, thus preventing their differentiation and the formation of
fibrofatty infiltration. The clearance of these cells is mediated by
Ly6C+ MPs through the secretion of TNFα (Lemos et al., 2015). In
contrast, TGFβ, an anti-inflammatory cytokine mainly secreted by
Ly6C− MPs at later stages of regeneration, provides protection to
FAPs from apoptosis (Lemos et al., 2015), highlighting how crucial
the timing of the switch from Ly6C+ to Ly6C− MPs is for the
restoration of tissue function. This is also the case in the heart, where
FAPs and MPs collaborate in the response to damage (Wang et al.,
2015). Notably, this switch may be perturbed in the context of
regenerative diseases such as Duchenne Muscular Dystrophy (DMD;
see Box 3).
Cardiac muscle repair
Cardiac damage, such as myocardial infarction, triggers massive
inflammation. However, in this context, tissue-resident MPs die at
the site of damage and the infiltration of new MPs that give rise to
tissue-resident MPs is required for cardiac tissue repair (Heidt et al.,
2014). As in other tissues, it is now accepted that damage recruits a
unique wave of Ly6C+ MOs, followed by their skewing into a
Ly6C− profile (Fig. 6B; Hilgendorf et al., 2014, Pinto et al., 2014;
Frangogiannis, 2015).
Consistent with the role of MPs in supporting cardiac
angiogenesis during neonatal development, infiltrated MPs are
capable of stimulating cardiac angiogenesis following perinatal
ischemic damage (Aurora et al., 2014). However, in adult infarction,
Development (2019) 146, dev156000. doi:10.1242/dev.156000
Box 3. Macrophage functions in degenerative disease –
DMD as a case study
In some pathologies, tissue regeneration is impaired. For example,
degenerative myopathies, such as Duchenne Muscular Dystrophy
(DMD), are muscle diseases associated with a continuous succession
of degeneration/regeneration cycles, eventually leading to disruption of
the regenerative process and alterations to the fate and function of
multiple cell types (Dadgar et al., 2014). DMD is associated with
increases in inflammatory cells, cytokines, fibrosis and lipid droplets
(Petrof et al., 1993; Barton, 2006; Desguerre et al., 2012). In this context,
a clear role for inflammatory cells in modulating fibrosis has been shown.
For example, whereas MPs act to clear stromal progenitors in the context
of normal skeletal muscle regeneration, MPs found in chronically
damaged muscle, despite being similar to early MPs in terms of
surface phenotype, promote fibro/adipocytic progenitor survival and
fibrogenic differentiation (Lemos et al., 2015; Juban et al., 2018).
Interestingly, this phenotype may be reversed by treating mice with
metformin, an activator of AMPK (an enzyme involved in MP-skewing
following acute damage; Mounier et al., 2013). Thus, the failure of
skeletal muscle regeneration in muscular dystrophies may be due to a
disruption of the carefully timed switch from a pro-inflammatory
environment to a pro-regenerative environment normally observed in
response to acute damage. Indeed, in chronic disease, the
asynchronous nature of the damage leads to contrasting signals being
present within the muscle at the same time. This is likely to impair the
functions of both myogenic and stromal progenitors, resulting in
disrupted regeneration and fibrofatty infiltration (Dadgar et al., 2014;
Tidball et al., 2014; Lemos et al., 2015; Tidball, 2017; Juban et al., 2018).
In the future, a better understanding of MP functions and gene
expression profiles in chronic disease is likely to lead to novel
therapeutic approaches for chronic disease.
MPs mainly promote matrix deposition and support scarring
(Fig. 6B) (Aurora et al., 2014). These differences in MP function
in neonatal versus adult heart repair could be because of distinct
phenotypes of MPs. Indeed, at least some tissue-resident MPs in the
heart are of embryonic origin, and are phenotypically more similar
to Ly6C− MPs than to Ly6C+ MPs (Aurora et al., 2014). Again,
depletion of tissue-resident or infiltrating MPs before or following
cardiac injury has been performed in many ways. Whereas depletion
of circulating MOs at an early point in repair negatively affects
cardiac repair, depleting them late after myocardial infarction in fact
improves cardiac recovery, highlighting the changing roles that
these cells play at different stages of the response to damage (Van
Amerongen et al., 2007; Heidt et al., 2014; Sager et al., 2016).
Moreover, depletion of tissue-resident MPs using CX3CR1-DTR
mice affects cardiac repair after myocardial infarction in the adult.
This appears to be because of the massive infiltration of new MPs
and the proliferation of the remaining tissue-resident MPs (Dick
et al., 2019). To conclude, it appears that both tissue-resident MPs
and infiltrating MPs have important functions in cardiac repair, and
boosting one or the other systems at a precise time could be a
potentially useful therapeutic tool.
DEVELOPMENT
Skin and hair growth/repair
Following skin damage, MPs are recruited and actively participate
in wound healing (Fig. 6C). Ly6C+ MOs infiltrate the skin,
providing immune protection against external pathogens, but also
act on stromal cells, keratinocytes and endothelial cells (Wang et al.,
2017). Again, depletion of circulating MOs using GM-CSF-KO,
CD11b-DTR or CCR2-KO mice highlights their importance in this
process (Fang et al., 2007; Mirza et al., 2009). Indeed, angiogenesis
is strongly decreased owing to CD31+ cell apoptosis (likely because
9
REVIEW
of decreases in TGFβ and VEGF secretion), strongly delaying
wound healing (Lucas et al., 2010). Infiltration of circulating MOs
(and other immune cells) to the site of healing is driven by activated
keratinocytes and the secretion of several chemokines such as
CXCL10, CXCL11, CCL5 and CCL20 (Banno et al., 2004). In
return, MPs activate keratinocyte proliferation and reepithelization
via the secretion of members of the epidermal growth factor (EGF)
family (Hancock et al., 1988; Shirakata, 2005). Although this direct
interaction has been demonstrated in vitro, it is not as clear-cut in
vivo (Grose and Werner, 2004).
Interestingly, wound-induced macrophages acquire a profile that
differs from the aforementioned Ly6C+/Ly6C− progression that is
observed in other tissues. Indeed, from day 1 to day 7 after
wounding, MPs express CD206, arginase 1 and Ym1 (Chil3),
which are markers typical of pro-regenerative cells that appear at
later stages of regeneration in other tissues (Mounier et al., 2013).
However, IL4 and IL13, which are cytokines described as being
required for an alternative MP activation pathway, are not present in
the wound, which suggest that other types of cytokines must be at
play. Ly6C and TNFα are downregulated, whereas the secretion of
TGFβ and VEGF is increased to accelerate the process of wound
healing, as described above for muscle (Daley et al., 2010). TNFα
secreted by MPs is important for the activation of hair follicle stem
cells after damage (Wang et al., 2017). Indeed, whereas TNFα-
deficient mice show delays in hair growth, TNFα actually stimulates
the telogen-anagen transition required for hair growth (Wang et al.,
2017). To conclude, during wound healing, MPs are the source of
multiple cytokines and growth factors acting on hair follicle stem
cells, endothelial cells and keratinocytes.
Liver regeneration
Infiltrating MPs play unique functional roles in both the resting and
regenerating liver (Fig. 6D). For example, Ly6C+ MOs engulf stressed
red blood cells in the bloodstream or the spleen, migrate to the liver and
differentiate into Ly6C+ MPs in a process supported by CCL2, CCL3,
and Csf1 released from Kupffer cells. These iron-charged MPs express
high levels of ferroportin1, allowing them to dispense iron to
hepatocytes (Gammella et al., 2014; Theurl et al., 2016).
As in most other tissues, MPs play key roles during regeneration
in the liver, and undergo a skewing process essentially identical to
that described for skeletal muscle, and likely just as important.
CD11b-DTR-mediated myelomonocytic cell depletion at the early
stages (the acute damage phase) of regeneration leads to reduced
fibrosis, whereas depletion at late stages (the recovery phase) leads
to the impairment of matrix degradation, inducing more fibrosis
(Duffield et al., 2005). It has also been shown that blood-derived
Ly6C− MPs are present in large numbers during fibrosis resolution,
which they likely promote through their secretion of MMP enzymes
(Ramachandran et al., 2012). In CCR2-deficient mice, in which MO
infiltration is reduced, damage-induced liver fibrosis is increased, as
occurs in the case of cardiac and skeletal muscle, suggesting that
loss of the matrix remodeling function of Ly6C− cells has a
dominant effect (Mitchell et al., 2009). As in most other tissues that
have been analyzed, liver MPs also directly influence the function of
tissue-specific stem/progenitor cells. For example, it was
demonstrated that, in a model of biliary and hepatocyte
regeneration, blood-derived MPs secrete Wnt ligands and remodel
extracellular matrix to induce hepatocyte differentiation of
progenitor cells (Boulter et al., 2012). After the resolution of
inflammation, it is possible that blood-derived MPs replace the
missing Kupffer cells, thereby maintaining a pool of tissue-resident
MPs ready for further needs (Blériot et al., 2015).
Development (2019) 146, dev156000. doi:10.1242/dev.156000
Chronic inflammation and disease
The roles of MPs in disease are so varied that it is not possible to
provide a full and comprehensive review here. However, as these
cells are crucially important in many human afflictions, we have
selected below a few examples, illustrating their non-immune
functions in pathological conditions, and their interactions with
tissue-resident stem cells in these contexts.
Type II diabetes, which is associated with obesity, is on the rise and
accounts for a significant number of deaths every year. Obesity is
associated with inflammation, and an accumulation of MPs in
adipose tissue is thought to predispose to insulin resistance (Weisberg
et al., 2003). In this context, it is of interest that high fat diet-induced
insulin resistance is reduced in mice lacking the myelomonocytic
integrin CD11b, and this correlates with an increase in adipose tissue-
resident MP proliferation and an inhibition of MO recruitment from
the circulation (Zheng et al., 2015). This suggests that Ly6C+ MPs
freshly immigrated from the bloodstream may play a pathogenic role
in Type II diabetes. Consistent with the idea that they modulate
adipose metabolism, MPs have been proposed to contribute to
thermogenesis regulation in brown adipose tissue by secreting
catecholamine, although this controversial notion has recently been
questioned (Nguyen et al., 2011; Fischer et al., 2017).
Obesity also causes adipocyte apoptosis and thus damages the
signals that attract Ly6C+ MOs, leading to their significant increase
in white adipose tissue. This may further contribute to adipocyte
enlargement and apoptosis, perpetuating a vicious circle (Sun et al.,
2011). As Ly6C+ MPs engulf dead adipocytes, they become
engorged by fatty acids, resulting in the adoption of a highly
inflammatory phenotype including secretion of TNFα and/or IL6.
This increase in inflammatory cytokines in the blood stream results
in chronic systemic inflammation and contributes to insulin
resistance (Lumeng et al., 2007). Thus, increasing the skewing of
MPs into a more mature phenotype (Ly6C−) may represent a
promising therapy to treat obesity-induced chronic inflammation
and its effects.
Tissue-resident MPs in the liver, Kupffer cells, are also involved
in metabolic homeostasis and related pathologies. Kupffer cells
secrete high levels of IL4 and IL13, possibly because of their low
levels of PPARγ, a transcription factor that promotes the acquisition
of an anti-inflammatory phenotype and the loss of Ly6C. The
acquisition of this pro-inflammatory phenotype contributes to
activating fatty acid oxidation by hepatocytes and eventually leads
to liver failure due to lipid accumulation (Kang et al., 2008;
Odegaard et al., 2008).
MPs also play a key role in the pathogenesis of autoimmune
metabolic diseases. For example, pancreatic islets of Type II diabetic
patients and rodent models are massively infiltrated by Ly6C+ MOs
and MPs, likely attracted by cytokines produced locally by
autoimmune T cells. In turn, IL1β, CCL2 and CX3CL1 released
from these Ly6C+ MPs contribute to pancreatic dysfunction by
recruiting new inflammatory TNFα-secreting Ly6C+ MOs, and
possibly starting a vicious cycle (Ehses et al., 2007).
In summary, it appears likely that MPs mediate a number of the
DEVELOPMENT
pathogenic effects that inflammation has on metabolism, and
patients may benefit from treatments modulating the functional state
of these cells.
Conclusions and perspectives
The more we study MPs, the more we realize that the early simplistic
views of these cells as ‘bug gobblers’ only describes a small portion
of their core functions. Indeed, we now know that these cells act as a
distinct disseminated tissue that is capable of influencing the local
10
REVIEW
microenvironment as well as priming the systemic response to
various types of damage. Acting via the carefully timed secretion of
a variety of molecular signals that modulate the activity of tissue-
resident cells, notably stem cells, MPs are involved in a large
number of developmental processes. Importantly, they also play key
roles in most events that lead to the reactivation of such processes,
including during adult regeneration and in the context of disease. In
line with these diverse functions, it is becoming apparent that MPs
are far more heterogeneous and significantly more complex than can
be captured by current classifications. The deployment of emerging
technologies allowing high-throughput single cell analysis will
be required to match phenotype to function and to identify
interventions that may modulate them specifically.
Acknowledgements
We thank Andrew Hagner for inspiring discussions. Some images of cell types,
organs and tissues were obtained from smart.servier.com and modified.
Competing interests
The authors declare no competing or financial interests.
Funding
This work was supported by the Fondation pour la Recherche Mé dicale (FRM; 40248
to M.T.); European Molecular Biology Organization (EMBO; ALTF 115-2016 to
M.T.); and the Canadian Institutes of Health Research (CIHR-FDN-159908 to F.R.).
References
Adolfsson, J., Månsson, R., Buza-Vidas, N., Hultquist, A., Liuba, K., Jensen,
C. T., Bryder, D., Yang, L., Borge, O.-J., Thoren, L. A. M. et al. (2005).
Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic
potential: a revised road map for adult blood lineage commitment. Cell 121,
295-306. doi:10.1016/j.cell.2005.02.013
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. and Rossi, F. M. V. (2007). Local
self-renewal can sustain CNS microglia maintenance and function throughout
adult life. Nat. Neurosci. 10, 1538-1543. doi:10.1038/nn2014
Alliot, F., Godin, I. and Pessac, B. (1999). Microglia derive from progenitors,
originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev.
Brain Res. 117, 145-152. doi:10.1016/S0165-3806(99)00113-3
Arnold, L., Henry, A., Poron, F., Baba-Amer, Y., Van Rooijen, N., Plonquet, A.,
Gherardi, R. K. and Chazaud, B. (2007). Inflammatory monocytes recruited after
skeletal muscle injury switch into antiinflammatory macrophages to support
myogenesis. J. Exp. Med. 204, 1057-1069. doi:10.1084/jem.20070075
Aurora, A. B., Porrello, E. R., Tan, W., Mahmoud, A. I., Hill, J. A., Bassel-Duby,
R., Sadek, H. A. and Olson, E. N. (2014). Macrophages are required for neonatal
heart regeneration. J. Clin. Invest. 124, 1382-1392. doi:10.1172/JCI72181
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh,
Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T. et al. (2018).
Epigenetic regulation of brain region-specific microglia clearance activity. Nat.
Neurosci. 21, 1049-1060. doi:10.1038/s41593-018-0192-3
Aziz, A., Soucie, E., Sarrazin, S. and Sieweke, M. H. (2009). MafB/c-Maf
deficiency enables self-renewal of differentiated functional macrophages. Science
326, 867-871. doi:10.1126/science.1176056
Banno, T., Gazel, A. and Blumenberg, M. (2004). Effects of tumor necrosis factor-α
(TNFα) in epidermal keratinocytes revealed using global transcriptional profiling.
J. Biol. Chem. 279, 32633-32642. doi:10.1074/jbc.M400642200
Barton, E. R. (2006). Impact of sarcoglycan complex on mechanical signal
transduction in murine skeletal muscle. Am. J. Physiol. Cell Physiol. 290,
C411-C419. doi:10.1152/ajpcell.00192.2005
Blé riot, C., Dupuis, T., Jouvion, G., Eberl, G., Disson, O. and Lecuit, M. (2015).
Liver-resident macrophage necroptosis orchestrates type 1 microbicidal
inflammation and type-2-mediated tissue repair during bacterial infection.
Immunity 42, 145-158. doi:10.1016/j.immuni.2014.12.020
Boring, L., Gosling, J., Chensue, S. W., Kunkel, S. L., Farese, R. V., Broxmeyer,
H. E. and Charo, I. F. (1997). Impaired monocyte migration and reduced type 1
(Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin.
Invest. 100, 2552-2561. doi:10.1172/JCI119798
Boulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P.,
Pellicoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N. et al.
(2012). Macrophage-derived Wnt opposes Notch signaling to specify hepatic
progenitor cell fate in chronic liver disease. Nat. Med. 18, 572-579. doi:10.1038/
nm.2667
Carlin, L. M., Stamatiades, E. G., Auffray, C., Hanna, R. N., Glover, L., Vizcay-
Barrena, G., Hedrick, C. C., Cook, H. T., Diebold, S. and Geissmann, F. (2013).
Development (2019) 146, dev156000. doi:10.1242/dev.156000
Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate
their disposal. Cell 153, 362-375. doi:10.1016/j.cell.2013.03.010
Castellana, D., Paus, R. and Perez-Moreno, M. (2014). Macrophages contribute to
the cyclic activation of adult hair follicle stem cells. PLoS Biol. 12, e1002002.
doi:10.1371/journal.pbio.1002002
Cavaillon, J.-M. (2011). The historical milestones in the understanding of leukocyte
biology initiated by Elie Metchnikoff. J. Leukoc. Biol. 90, 413-424. doi:10.1189/jlb.
0211094
Chan, W. Y., Kohsaka, S. and Rezaie, P. (2007). The origin and cell lineage of
microglia: new concepts. Brain Res. Rev. 53, 344-354. doi:10.1016/j.brainresrev.
2006.11.002
Chen, C.-C., Wang, L., Plikus, M. V., Jiang, T. X., Murray, P. J., Ramos, R.,
Guerrero-Juarez, C. F., Hughes, M. W., Lee, O. K., Shi, S. et al. (2015). Organ-
level quorum sensing directs regeneration in hair stem cell populations. Cell 161,
277-290. doi:10.1016/j.cell.2015.02.016
Chow, A., Huggins, M., Ahmed, J., Hashimoto, D., Lucas, D., Kunisaki, Y.,
Pinho, S., Leboeuf, M., Noizat, C., Van Rooijen, N. et al. (2013). CD169(+)
macrophages provide a niche promoting erythropoiesis under homeostasis and
stress. Nat. Med. 19, 429-436. doi:10.1038/nm.3057
Dadgar, S., Wang, Z., Johnston, H., Kesari, A., Nagaraju, K., Chen, Y.-W., Hill,
D. A., Partridge, T. A., Giri, M., Freishtat, R. J. et al. (2014). Asynchronous
remodeling is a driver of failed regeneration in Duchenne muscular dystrophy.
J. Cell Biol. 207, 139-158. doi:10.1083/jcb.201402079
Dai, X.-M., Ryan, G. R., Hapel, A. J., Dominguez, M. G., Russell, R. G., Kapp, S.,
Sylvestre, V. and Stanley, E. R. (2002). Targeted disruption of the mouse colony-
stimulating factor 1 receptor gene results in osteopetrosis, mononuclear
phagocyte deficiency, increased primitive progenitor cell frequencies, and
reproductive defects. Blood 99, 111-120. doi:10.1182/blood.V99.1.111
Dakic, A., Metcalf, D., Di Rago, L., Mifsud, S., Wu, L. and Nutt, S. L. (2005). PU.1
regulates the commitment of adult hematopoietic progenitors and restricts
granulopoiesis. J. Exp. Med. 201, 1487-1502. doi:10.1084/jem.20050075
Daley, J. M., Brancato, S. K., Thomay, A. A., Reichner, J. S. and Albina, J. E.
(2010). The phenotype of murine wound macrophages. J. Leukoc. Biol. 87, 59-67.
doi:10.1189/jlb.0409236
Davies, L. C., Jenkins, S. J., Allen, J. E. and Taylor, P. R. (2013). Tissue-resident
macrophages. Nat. Immunol. 14, 986-995. doi:10.1038/ni.2705
Dekoter, R. P., Walsh, J. C. and Singh, H. (1998). PU.1 regulates both cytokine-
dependent proliferation and differentiation of granulocyte/macrophage
progenitors. EMBO J. 17, 4456-4468. doi:10.1093/emboj/17.15.4456
Del Rio-Hortega, P. (1932). Microglia. In Cytology and cellular pathology of the
nervous system (ed. W. Penfield), pp. 483-534. New York: P.B. Hoeber.
Desguerre, I., Arnold, L., Vignaud, A., Cuvellier, S., Yacoub-Youssef, H.,
Gherardi, R. K., Chelly, J., Chretien, F., Mounier, R., Ferry, A. et al. (2012). A
new model of experimental fibrosis in hindlimb skeletal muscle of adult mdx
mouse mimicking muscular dystrophy. Muscle Nerve 45, 803-814. doi:10.1002/
mus.23341
Desvergne, B. (2008). PPARdelta/beta: the lobbyist switching macrophage
allegiance in favor of metabolism. Cell Metab. 7, 467-469. doi:10.1016/j.cmet.
2008.05.002
Di Meglio, P., Perera, G. K. and Nestle, F. O. (2011). The multitasking organ: recent
insights into skin immune function. Immunity 35, 857-869. doi:10.1016/j.immuni.
2011.12.003
Dick, S. A., Macklin, J. A., Nejat, S., Momen, A., Clemente-Casares, X.,
Althagafi, M. G., Chen, J., Kantores, C., Hosseinzadeh, S., Aronoff, L. et al.
(2019). Self-renewing resident cardiac macrophages limit adverse remodeling
following myocardial infarction. Nat. Immunol. 20, 29-39. doi:10.1038/s41590-
018-0272-2
Doebel, T., Voisin, B. and Nagao, K. (2017). Langerhans cells – the macrophage in
dendritic cell clothing. Trends Immunol. 38, 817-828. doi:10.1016/j.it.2017.06.008
Drissen, R., Buza-Vidas, N., Woll, P., Thongjuea, S., Gambardella, A.,
Giustacchini, A., Mancini, E., Zriwil, A., Lutteropp, M., Grover, A. et al.
(2016). Distinct myeloid progenitor-differentiation pathways identified through
single-cell RNA sequencing. Nat. Immunol. 17, 666-676. doi:10.1038/ni.3412
Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M.,
Vuthoori, S., Wu, S., Lang, R. and Iredale, J. P. (2005). Selective depletion of
macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin.
Invest. 115, 56-65. doi:10.1172/JCI200522675
DEVELOPMENT
Dzierzak, E. and Robin, C. (2010). Placenta as a source of hematopoietic stem
cells. Trends Mol. Med. 16, 361-367. doi:10.1016/j.molmed.2010.05.005
Ehses, J. A., Perren, A., Eppler, E., Ribaux, P., Pospisilik, J. A., Maor-Cahn, R.,
Gueripel, X., Ellingsgaard, H., Schneider, M. K. J., Biollaz, G. et al. (2007).
Increased number of islet-associated macrophages in type 2 diabetes. Diabetes
56, 2356-2370. doi:10.2337/db06-1650
Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E.,
Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L. et al. (2014).
Colony-stimulating factor 1 receptor signaling is necessary for microglia viability,
unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380-397.
doi:10.1016/j.neuron.2014.02.040
11
REVIEW
Engelhardt, B. and Ransohoff, R. M. (2012). Capture, crawl, cross: The T cell code
to breach the blood-brain barriers. Trends Immunol. 33, 579-589. doi:10.1016/j.it.
2012.07.004
Epelman, S., Lavine, K. J., Beaudin, A. E., Sojka, D. K., Carrero, J. A., Calderon,
B., Brija, T., Gautier, E. L., Ivanov, S., Satpathy, A. T. et al. (2014a). Embryonic
and adult-derived resident cardiac macrophages are maintained through distinct
mechanisms at steady state and during inflammation. Immunity 40, 91-104.
doi:10.1016/j.immuni.2013.11.019
Epelman, S., Lavine, K. J. and Randolph, G. J. (2014b). Origin and functions of
tissue macrophages. Immunity 41, 21-35. doi:10.1016/j.immuni.2014.06.013
Erblich, B., Zhu, L., Etgen, A. M., Dobrenis, K. and Pollard, J. W. (2011). Absence
of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain
development and olfactory deficits. PloS one 6, e26317. doi:10.1371/journal.
pone.0026317
Fang, Y., Gong, S.-J., Xu, Y.-H., Hambly, B. D. and Bao, S. (2007). Impaired
cutaneous wound healing in granulocyte/ macrophage colony-stimulating factor
knockout mice. Br. J. Dermatol. 157, 458-465. doi:10.1111/j.1365-2133.2007.
07979.x
Fantin, A., Vieira, J. M., Gestri, G., Denti, L., Schwarz, Q., Prykhozhij, S., Peri, F.,
Wilson, S. W. and Ruhrberg, C. (2010). Tissue macrophages act as cellular
chaperones for vascular anastomosis downstream of VEGF-mediated endothelial
tip cell induction. Blood 116, 829-840. doi:10.1182/blood-2009-12-257832
Fischer, K., Ruiz, H. H., Jhun, K., Finan, B., Oberlin, D. J., Van Der Heide, V.,
Kalinovich, A. V., Petrovic, N., Wolf, Y., Clemmensen, C. et al. (2017).
Alternatively activated macrophages do not synthesize catecholamines or
contribute to adipose tissue adaptive thermogenesis. Nat. Med. 23, 623-630.
doi:10.1038/nm.4316
Frangogiannis, N. G. (2015). Inflammation in cardiac injury, repair and regeneration.
Curr. Opin. Cardiol. 30, 240-245. doi:10.1097/HCO.0000000000000158
Freire-De-Lima, C. G., Nascimento, D. O., Soares, M. B. P., Bozza, P. T., Castro-
Faria-Neto, H. C., De Mello, F. G., Dosreis, G. A. and Lopes, M. F. (2000).
Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in
macrophages. Nature 403, 199-203. doi:10.1038/35003208
Gammella, E., Buratti, P., Cairo, G. and Recalcati, S. (2014). Macrophages:
central regulators of iron balance. Metallomics 6, 1336-1345. doi:10.1039/
C4MT00104D
Gautier, E. L. and Yvan-Charvet, L. (2014). Understanding macrophage diversity
at the ontogenic and transcriptomic levels. Immunol. Rev. 262, 85-95. doi:10.
1111/imr.12231
Geissmann, F., Jung, S. and Littman, D. R. (2003). Blood monocytes consist of
two principal subsets with distinct migratory properties. Immunity 19, 71-82.
doi:10.1016/S1074-7613(03)00174-2
Ginhoux, F. and Guilliams, M. (2016). Tissue-resident macrophage ontogeny and
homeostasis. Immunity 44, 439-449. doi:10.1016/j.immuni.2016.02.024
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler,
M. F., Conway, S. J., Ng, L. G., Stanley, E. R. et al. (2010). Fate mapping
analysis reveals that adult microglia derive from primitive macrophages. Science
330, 841-845. doi:10.1126/science.1194637
Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet,
L., Garner, H., Trouillet, C., De Bruijn, M. F., Geissmann, F. et al. (2015).
Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid
progenitors. Nature 518, 547-551. doi:10.1038/nature13989
Graeber, M. B. and Streit, W. J. (2010). Microglia: biology and pathology. Acta
Neuropathol. 119, 89-105. doi:10.1007/s00401-009-0622-0
Grose, R. and Werner, S. (2004). Wound-healing studies in transgenic and
knockout mice. Appl. Biochem. Biotechnol. B Mol. Biotechnol. 28, 147-166.
doi:10.1385/MB:28:2:147
Guilliams, M. and Scott, C. L. (2017). Does niche competition determine the origin
of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451-460. doi:10.1038/
nri.2017.42
Guilliams, M., De Kleer, I., Henri, S., Post, S., Vanhoutte, L., De Prijck, S.,
Deswarte, K., Malissen, B., Hammad, H. and Lambrecht, B. N. (2013). Alveolar
macrophages develop from fetal monocytes that differentiate into long-lived cells
in the first week of life via GM-CSF. J. Exp. Med. 210, 1977-1992. doi:10.1084/
jem.20131199
Gustafsson, K. and Welsh, M. (2016). Maintenance of hematopoietic stem cell
dormancy: yet another role for the macrophage. Stem Cell Investig. 3, 46. doi:10.
21037/sci.2016.08.10
Hammond, T. R., Robinton, D. and Stevens, B. (2018). Microglia and the brain:
complementary partners in development and disease. Annu. Rev. Cell Dev. Biol.
34, 523-544. doi:10.1146/annurev-cellbio-100616-060509
Hancock, G. E., Kaplan, G. and Cohn, Z. (1988). Keratinocyte growth regulation by
the products of immune cells. J. Exp. Med. 168, 1395-1402. doi:10.1084/jem.168.
4.1395
Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M. B., Leboeuf, M., Becker,
C. D., See, P., Price, J., Lucas, D. et al. (2013). Tissue-resident macrophages self-
maintain locally throughout adult life with minimal contribution from circulating
monocytes. Immunity 38, 792-804. doi:10.1016/j.immuni.2013.04.004
Heidt, T., Courties, G., Dutta, P., Sager, H. B., Sebas, M., Iwamoto, Y., Sun, Y., Da
Silva, N., Panizzi, P., Van Der Laan, A. M. et al. (2014). Differential contribution
Development (2019) 146, dev156000. doi:10.1242/dev.156000
of monocytes to heart macrophages in steady-state and after myocardial
infarction. Circ. Res. 115, 284-295. doi:10.1161/CIRCRESAHA.115.303567
Hellwig, S., Heinrich, A. and Biber, K. (2013). The brain’s best friend: microglial
neurotoxicity revisited. Front. Cell. Neurosci. 7, 71. doi:10.3389/fncel.2013.00071
Henri, S., Poulin, L. F., Tamoutounour, S., Ardouin, L., Guilliams, M., De Bovis,
B., Devilard, E., Viret, C., Azukizawa, H., Kissenpfennig, A. et al. (2010).
CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived
antigens irrespective of the presence of Langerhans cells. J. Exp. Med. 207,
189-206. doi:10.1084/jem.20091964
Herbomel, P., Thisse, B. and Thisse, C. (2001). Zebrafish early macrophages
colonize cephalic mesenchyme and developing brain, retina, and epidermis
through a M-CSF receptor-dependent invasive process. Dev. Biol. 238, 274-288.
doi:10.1006/dbio.2001.0393
Hilgendorf, I., Gerhardt, L. M. S., Tan, T. C., Winter, C., Holderried, T. A. W.,
Chousterman, B. G., Iwamoto, Y., Liao, R., Zirlik, A., Scherer-Crosbie, M.
et al. (2014). Ly-6Chigh monocytes depend on Nr4a1 to balance both
inflammatory and reparative phases in the infarcted myocardium. Circ. Res.
114, 1611-1622. doi:10.1161/CIRCRESAHA.114.303204
Hoeffel, G. and Ginhoux, F. (2015). Ontogeny of tissue-resident macrophages.
Front. Immunol. 6, 486. doi:10.3389/fimmu.2015.00486
Hoeffel, G., Wang, Y., Greter, M., See, P., Teo, P., Malleret, B., Leboeuf, M., Low,
D., Oller, G., Almeida, F. et al. (2012). Adult Langerhans cells derive
predominantly from embryonic fetal liver monocytes with a minor contribution of
yolk sac-derived macrophages. J. Exp. Med. 209, 1167-1181. doi:10.1084/jem.
20120340
Huang, Y., Xu, Z., Xiong, S., Sun, F., Qin, G., Hu, G., Wang, J., Zhao, L., Liang, Y.-
X., Wu, T. et al. (2018). Repopulated microglia are solely derived from the
proliferation of residual microglia after acute depletion. Nat. Neurosci. 21,
530-540. doi:10.1038/s41593-018-0090-8
Hulsmans, M., Clauss, S., Xiao, L., Aguirre, A. D., King, K. R., Hanley, A.,
Hucker, W. J., Wü lfers, E. M., Seemann, G., Courties, G. et al. (2017).
Macrophages facilitate electrical conduction in the heart. Cell 169, 510-522.e20.
doi:10.1016/j.cell.2017.03.050
Jackaman, C., Tomay, F., Duong, L., Abdol Razak, N. B., Pixley, F. J., Metharom,
P. and Nelson, D. J. (2017). Aging and cancer: the role of macrophages and
neutrophils. Ageing Res. Rev. 36, 105-116. doi:10.1016/j.arr.2017.03.008
Jakubzick, C., Gautier, E. L., Gibbings, S. L., Sojka, D. K., Schlitzer, A.,
Johnson, T. E., Ivanov, S., Duan, Q., Bala, S., Condon, T. et al. (2013). Minimal
differentiation of classical monocytes as they survey steady-state tissues and
transport antigen to lymph nodes. Immunity 39, 599-610. doi:10.1016/j.immuni.
2013.08.007
Jenkins, S. J. and Hume, D. A. (2014). Homeostasis in the mononuclear
phagocyte system. Trends Immunol. 35, 358-367. doi:10.1016/j.it.2014.06.006
Johann, A. M., Von Knethen, A., Lindemann, D. and Brü ne, B. (2006).
Recognition of apoptotic cells by macrophages activates the peroxisome
proliferator-activated receptor-gamma and attenuates the oxidative burst. Cell
Death Differ. 13, 1533-1540. doi:10.1038/sj.cdd.4401832
Juban, G., Saclier, M., Yacoub-Youssef, H., Kernou, A., Arnold, L., Boisson, C.,
Ben Larbi, S., Magnan, M., Cuvellier, S., Thé ret, M. et al. (2018). AMPK
activation regulates LTBP4-dependent TGF-beta1 secretion by pro-inflammatory
macrophages and controls fibrosis in Duchenne muscular dystrophy. Cell Rep. 25,
2163-2176.e6. doi:10.1016/j.celrep.2018.10.077
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A.
and Littman, D. R. (2000). Analysis of fractalkine receptor CX(3)CR1 function by
targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell.
Biol. 20, 4106-4114. doi:10.1128/MCB.20.11.4106-4114.2000
Kang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B.
and Lee, C.-H. (2008). Adipocyte-derived Th2 cytokines and myeloid PPARdelta
regulate macrophage polarization and insulin sensitivity. Cell Metab. 7, 485-495.
doi:10.1016/j.cmet.2008.04.002
Khan, T. N., Wong, E. B., Soni, C. and Rahman, Z. S. M. (2013). Prolonged
apoptotic cell accumulation in germinal centers of Mer-deficient mice causes
elevated B cell and CD4+ Th cell responses leading to autoantibody production.
J. Immunol. 190, 1433-1446. doi:10.4049/jimmunol.1200824
Kierdorf, K. and Dionne, M. S. (2016). The software and hardware of
macrophages: a diversity of options. Dev. Cell 38, 122-125. doi:10.1016/j.
devcel.2016.07.008
Kierdorf, K., Prinz, M., Geissmann, F. and Gomez Perdiguero, E. (2015).
DEVELOPMENT
Development and function of tissue resident macrophages in mice. Semin.
Immunol. 27, 369-378. doi:10.1016/j.smim.2016.03.017
Kohyama, M., Ise, W., Edelson, B. T., Wilker, P. R., Hildner, K., Mejia, C., Frazier,
W. A., Murphy, T. L. and Murphy, K. M. (2009). Role for Spi-C in the development
of red pulp macrophages and splenic iron homeostasis. Nature 457, 318-321.
doi:10.1038/nature07472
Latroche, C., Weiss-Gayet, M., Muller, L., Gitiaux, C., Leblanc, P., Liot, S., Ben-
Larbi, S., Abou-Khalil, R., Verger, N., Bardot, P. et al. (2017). Coupling between
myogenesis and angiogenesis during skeletal muscle regeneration is stimulated
by restorative macrophages. Stem Cell Rep. 9, 2018-2033. doi:10.1016/j.stemcr.
2017.10.027
12
REVIEW
Lehrman, E. K., Wilton, D. K., Litvina, E. Y., Welsh, C. A., Chang, S. T., Frouin,
A., Walker, A. J., Heller, M. D., Umemori, H., Chen, C. et al. (2018). CD47
protects synapses from excess microglia-mediated pruning during development.
Neuron 100, 120-134.e6. doi:10.1016/j.neuron.2018.09.017
Lemos, D. R., Babaeijandaghi, F., Low, M., Chang, C.-K., Lee, S. T., Fiore, D.,
Zhang, R.-H., Natarajan, A., Nedospasov, S. A. and Rossi, F. M. V. (2015).
Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-
mediated apoptosis of fibro/adipogenic progenitors. Nat. Med. 21, 786-794.
doi:10.1038/nm.3869
Ley, K. (2017). M1 means kill; M2 means heal. J. Immunol. 199, 2191-2193. doi:10.
4049/jimmunol.1701135
Linehan, E. and Fitzgerald, D. (2015). Ageing and the immune system: focus on
macrophages. Eur. J. Microbiol. Immunol. 5, 14-24. doi:10.1556/EuJMI-D-14-
00035
Lu, B., Rutledge, B. J., Gu, L., Fiorillo, J., Lukacs, N. W., Kunkel, S. L., North, R.,
Gerard, C. and Rollins, B. J. (1998). Abnormalities in monocyte recruitment and
cytokine expression in monocyte chemoattractant protein 1-deficient mice. J. Exp.
Med. 187, 601-608. doi:10.1084/jem.187.4.601
Lucas, T., Waisman, A., Ranjan, R., Roes, J., Krieg, T., Muller, W., Roers, A. and
Eming, S. A. (2010). Differential roles of macrophages in diverse phases of skin
repair. J. Immunol. 184, 3964-3977. doi:10.4049/jimmunol.0903356
Lumeng, C. N., Bodzin, J. L. and Saltiel, A. R. (2007). Obesity induces a
phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117,
175-184. doi:10.1172/JCI29881
Machiels, B., Dourcy, M., Xiao, X., Javaux, J., Mesnil, C., Sabatel, C., Desmecht,
D., Lallemand, F., Martinive, P., Hammad, H. et al. (2017). A gammaherpesvirus
provides protection against allergic asthma by inducing the replacement of
resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18,
1310-1320. doi:10.1038/ni.3857
Martinez, F. O., Sica, A., Mantovani, A. and Locati, M. (2008). Macrophage
activation and polarization. Front. Biosci. 13, 453-461. doi:10.2741/2692
Mass, E., Ballesteros, I., Farlik, M., Halbritter, F., Gunther, P., Crozet, L.,
Jacome-Galarza, C. E., Handler, K., Klughammer, J., Kobayashi, Y. et al.
(2016). Specification of tissue-resident macrophages during organogenesis.
Science 353, aaf4238. doi:10.1126/science.aaf4238
Mckercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J.,
Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J. et al. (1996).
Targeted disruption of the PU.1 gene results in multiple hematopoietic
abnormalities. EMBO J. 15, 5647-5658. doi:10.1002/j.1460-2075.1996.tb00949.x
Merad, M., Manz, M. G., Karsunky, H., Wagers, A., Peters, W., Charo, I.,
Weissman, I. L., Cyster, J. G. and Engleman, E. G. (2002). Langerhans cells
renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3,
1135-1141. doi:10.1038/ni852
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. and Hill, A. M. (2000). M-1/M-2
macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166-6173. doi:10.
1177/000271622310900111
Mirza, R., Dipietro, L. A. and Koh, T. J. (2009). Selective and specific macrophage
ablation is detrimental to wound healing in mice. Am. J. Pathol. 175, 2454-2462.
doi:10.2353/ajpath.2009.090248
Mitchell, C., Couton, D., Couty, J.-P., Anson, M., Crain, A.-M., Bizet, V., Ré nia, L.,
Pol, S., Mallet, V. and Gilgenkrantz, H. (2009). Dual role of CCR2 in the
constitution and the resolution of liver fibrosis in mice. Am. J. Pathol. 174,
1766-1775. doi:10.2353/ajpath.2009.080632
Mojumdar, K., Liang, F., Giordano, C., Lemaire, C., Danialou, G., Okazaki, T.,
Bourdon, J., Rafei, M., Galipeau, J., Divangahi, M. et al. (2014). Inflammatory
monocytes promote progression of Duchenne muscular dystrophy and can be
therapeutically targeted via CCR2. EMBO Mol. Med. 6, 1476-1492. doi:10.15252/
emmm.201403967
Molawi, K., Wolf, Y., Kandalla, P. K., Favret, J., Hagemeyer, N., Frenzel, K.,
Pinto, A. R., Klapproth, K., Henri, S., Malissen, B. et al. (2014). Progressive
replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211,
2151-2158. doi:10.1084/jem.20140639
Mounier, R., Thé ret, M., Arnold, L., Cuvellier, S., Bultot, L., Gö ransson, O.,
Sanz, N., Ferry, A., Sakamoto, K., Foretz, M. et al. (2013). AMPKalpha1
regulates macrophage skewing at the time of resolution of inflammation during
skeletal muscle regeneration. Cell Metab. 18, 251-264. doi:10.1016/j.cmet.2013.
06.017
Nguyen, K. D., Qiu, Y., Cui, X., Goh, Y. P. S., Mwangi, J., David, T., Mukundan, L.,
Brombacher, F., Locksley, R. M. and Chawla, A. (2011). Alternatively activated
macrophages produce catecholamines to sustain adaptive thermogenesis.
Nature 480, 104-108. doi:10.1038/nature10653
Nguyen-Lefebvre, A. T. and Horuzsko, A. (2015). Kupffer cell metabolism and
function. J. Enzymol. Metab. 1, 101.
Notta, F., Zandi, S., Takayama, N., Dobson, S., Gan, O. I., Wilson, G., Kaufmann,
K. B., Mcleod, J., Laurenti, E., Dunant, C. F. et al. (2016). Distinct routes of
lineage development reshape the human blood hierarchy across ontogeny.
Science 351, aab2116. doi:10.1126/science.aab2116
Odegaard, J. I., Ricardo-Gonzalez, R. R., Red Eagle, A., Vats, D., Morel, C. R.,
Goforth, M. H., Subramanian, V., Mukundan, L., Ferrante, A. W. and Chawla,
A. (2008). Alternative M2 activation of Kupffer cells by PPARdelta ameliorates
Development (2019) 146, dev156000. doi:10.1242/dev.156000
obesity-induced insulin resistance. Cell Metab. 7, 496-507. doi:10.1016/j.cmet.
2008.04.003
Orkin, S. H. and Zon, L. I. (2008). Hematopoiesis: an evolving paradigm for stem
cell biology. Cell 132, 631-644. doi:10.1016/j.cell.2008.01.025
Osaka, N., Takahashi, T., Murakami, S., Matsuzawa, A., Noguchi, T., Fujiwara,
T., Aburatani, H., Moriyama, K., Takeda, K. and Ichijo, H. (2007). ASK1-
dependent recruitment and activation of macrophages induce hair growth in skin
wounds. J. Cell Biol. 176, 903-909. doi:10.1083/jcb.200611015
Palis, J. and Yoder, M. C. (2001). Yolk-sac hematopoiesis: the first blood cells of
mouse and man. Exp. Hematol. 29, 927-936. doi:10.1016/S0301-
472X(01)00669-5
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P.,
Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L. et al. (2011). Synaptic
pruning by microglia is necessary for normal brain development. Science 333,
1456-1458. doi:10.1126/science.1202529
Paus, R. (1998). Principles of hair cycle control. J. Dermatol. 25, 793-802. doi:10.
1111/j.1346-8138.1998.tb02507.x
Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M. and Sweeney, H. L.
(1993). Dystrophin protects the sarcolemma from stresses developed during
muscle contraction. Proc. Natl. Acad. Sci. USA 90, 3710-3714. doi:10.1073/pnas.
90.8.3710
Pinto, A. R., Godwin, J. W. and Rosenthal, N. A. (2014). Macrophages in cardiac
homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res.
13, 705-714. doi:10.1016/j.scr.2014.06.004
Porrello, E. R., Mahmoud, A. I., Simpson, E., Hill, J. A., Richardson, J. A., Olson,
E. N. and Sadek, H. A. (2011). Transient regenerative potential of the neonatal
mouse heart. Science 331, 1078-1080. doi:10.1126/science.1200708
Rahmani, W., Liu, Y., Rosin, N. L., Kline, A., Raharjo, E., Yoon, J., Stratton, J. A.,
Sinha, S. and Biernaskie, J. (2018). Macrophages promote wound-induced hair
follicle regeneration in a CX3CR1- and TGF-beta1-dependent manner. J. Invest.
Dermatol. 138, 2111-2122. doi:10.1016/j.jid.2018.04.010
Ramachandran, P., Pellicoro, A., Vernon, M. A., Boulter, L., Aucott, R. L., Ali, A.,
Hartland, S. N., Snowdon, V. K., Cappon, A., Gordon-Walker, T. T. et al.
(2012). Differential Ly-6C expression identifies the recruited macrophage
phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl.
Acad. Sci. USA 109, E3186-E3195. doi:10.1073/pnas.1119964109
Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, R. G.,
Rosenthal, N. and Nerlov, C. (2009). A CREB-C/EBPbeta cascade induces
M2 macrophage-specific gene expression and promotes muscle injury repair.
Proc. Natl. Acad. Sci. USA 106, 17475-17480. doi:10.1073/pnas.0908641106
Saclier, M., Yacoub-Youssef, H., Mackey, A. L., Arnold, L., Ardjoune, H.,
Magnan, M., Sailhan, F., Chelly, J., Pavlath, G. K., Mounier, R. et al. (2013a).
Differentially activated macrophages orchestrate myogenic precursor cell fate
during human skeletal muscle regeneration. Stem Cells 31, 384-396. doi:10.1002/
stem.1288
Saclier, M., Cuvellier, S., Magnan, M., Mounier, R. and Chazaud, B. (2013b).
Monocyte/macrophage interactions with myogenic precursor cells during skeletal
muscle regeneration. FEBS J. 280, 4118-4130. doi:10.1111/febs.12166
Sager, H. B., Hulsmans, M., Lavine, K. J., Moreira, M. B., Heidt, T., Courties, G.,
Sun, Y., Iwamoto, Y., Tricot, B., Khan, O. F. et al. (2016). Proliferation and
recruitment contribute to myocardial macrophage expansion in chronic heart
failure. Circ. Res. 119, 853-864. doi:10.1161/CIRCRESAHA.116.309001
Salter, M. W. and Beggs, S. (2014). Sublime microglia: expanding roles for the
guardians of the CNS. Cell 158, 15-24. doi:10.1016/j.cell.2014.06.008
Sarrazin, S. and Sieweke, M. H. (2016). Eosinophils and mast cells: a lineage apart.
Nat. Immunol. 17, 609-611. doi:10.1038/ni.3446
Schulz, C., Perdiguero, E. G., Chorro, L., Szabo-Rogers, H., Cagnard, N.,
Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W. et al. (2012). A
lineage of myeloid cells independent of Myb and hematopoietic stem cells.
Science 336, 86-90. doi:10.1126/science.1219179
Shirakata, Y. (2005). Heparin-binding EGF-like growth factor accelerates
keratinocyte migration and skin wound healing. J. Cell Sci. 118, 2363-2370.
doi:10.1242/jcs.02346
Sica, A., Erreni, M., Allavena, P. and Porta, C. (2015). Macrophage polarization in
pathology. Cell. Mol. Life Sci. 72, 4111-4126. doi:10.1007/s00018-015-1995-y
Sieweke, M. H. and Allen, J. E. (2013). Beyond stem cells: self-renewal of
differentiated macrophages. Science 342, 1242974. doi:10.1126/science.
1242974
DEVELOPMENT
Sonnet, C., Lafuste, P., Arnold, L., Brigitte, M., Poron, F., Authier, F. J., Chré tien,
F., Gherardi, R. K. and Chazaud, B. (2006). Human macrophages rescue
myoblasts and myotubes from apoptosis through a set of adhesion molecular
systems. J. Cell Sci. 119, 2497-2507. doi:10.1242/jcs.02988
Sun, K., Kusminski, C. M. and Scherer, P. E. (2011). Adipose tissue remodeling
and obesity. J. Clin. Invest. 121, 2094-2101. doi:10.1172/JCI45887
Tamoutounour, S., Guilliams, M., Montanana Sanchis, F., Liu, H., Terhorst, D.,
Malosse, C., Pollet, E., Ardouin, L., Luche, H., Sanchez, C. et al. (2013).
Origins and functional specialization of macrophages and of conventional and
monocyte-derived dendritic cells in mouse skin. Immunity 39, 925-938. doi:10.
1016/j.immuni.2013.10.004
13
REVIEW
Theurl, I., Hilgendorf, I., Nairz, M., Tymoszuk, P., Haschka, D., Asshoff, M., He,
S., Gerhardt, L. M. S., Holderried, T. A. W., Seifert, M. et al. (2016). On-demand
erythrocyte disposal and iron recycling requires transient macrophages in the
liver. Nat. Med. 22, 945-951. doi:10.1038/nm.4146
Tidball, J. G. (2017). Regulation of muscle growth and regeneration by the immune
system. Nat. Rev. Immunol. 17, 165-178. doi:10.1038/nri.2016.150
Tidball, J. G., Dorshkind, K. and Wehling-Henricks, M. (2014). Shared signaling
systems in myeloid cell-mediated muscle regeneration. Development 141,
1184-1196. doi:10.1242/dev.098285
Tonkin, J., Temmerman, L., Sampson, R. D., Gallego-Colon, E., Barberi, L.,
Bilbao, D., Schneider, M. D., Musarò, A. and Rosenthal, N. (2015). Monocyte/
macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and
modulates autocrine polarization. Mol. Ther. 23, 1189-1200. doi:10.1038/mt.2015.66
Tremblay, M.-E., Lowery, R. L. and Majewska, A. K. (2010). Microglial interactions
with synapses are modulated by visual experience. PLoS Biol. 8, e1000527.
doi:10.1371/journal.pbio.1000527
Van Amerongen, M. J., Harmsen, M. C., Van Rooijen, N., Petersen, A. H. and
Van Luyn, M. J. A. (2007). Macrophage depletion impairs wound healing and
increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol.
170, 818-829. doi:10.2353/ajpath.2007.060547
Van Furth, R. and Cohn, Z. A. (1968). The origin and kinetics of mononuclear
phagocytes. J. Exp. Med. 128, 415-435. doi:10.1084/jem.128.3.415
Varga, T., Mounier, R., Gogolak, P., Poliska, S., Chazaud, B. and Nagy, L.
(2013). Tissue LyC6- macrophages are generated in the absence of circulating
LyC6- monocytes and Nur77 in a model of muscle regeneration. J. Immunol. 191,
5695-5701. doi:10.4049/jimmunol.1301445
Varga, T., Mounier, R., Horvath, A., Cuvellier, S., Dumont, F., Poliska, S.,
Ardjoune, H., Juban, G., Nagy, L. and Chazaud, B. (2016a). Highly dynamic
transcriptional signature of distinct macrophage subsets during sterile
inflammation, resolution, and tissue repair. J. Immunol. 196, 4771-4782. doi:10.
4049/jimmunol.1502490
Varga, T., Mounier, R., Patsalos, A., Gogolá k, P., Peloquin, M., Horvath, A., Pap,
A., Daniel, B., Nagy, G., Pintye, E. et al. (2016b). Macrophage PPARgamma, a
lipid activated transcription factor controls the growth factor GDF3 and skeletal
muscle regeneration. Immunity 45, 1038-1051. doi:10.1016/j.immuni.2016.10.016
Varol, C., Vallon-Eberhard, A., Elinav, E., Aychek, T., Shapira, Y., Luche, H.,
Fehling, H. J., Hardt, W.-D., Shakhar, G. and Jung, S. (2009). Intestinal lamina
propria dendritic cell subsets have different origin and functions. Immunity 31,
502-512. doi:10.1016/j.immuni.2009.06.025
Von Kupffer, K. W. (1876). Ueber Sternzellen der Leber. Arch Mikroskop Anat. 12,
353-358. doi:10.1007/BF02933897
Development (2019) 146, dev156000. doi:10.1242/dev.156000
Wang, M., Zhang, G., Wang, Y., Liu, T., Zhang, Y., An, Y. and Li, Y. (2015).
Crosstalk of mesenchymal stem cells and macrophages promotes cardiac muscle
repair. Int. J. Biochem. Cell Biol. 58, 53-61. doi:10.1016/j.biocel.2014.11.003
Wang, X., Zhao, W., Ransohoff, R. M. and Zhou, L. (2016). Identification and
function of fibrocytes in skeletal muscle injury repair and muscular dystrophy.
J. Immunol. 197, 4750-4761. doi:10.4049/jimmunol.1601308
Wang, X., Chen, H., Tian, R., Zhang, Y., Drutskaya, M. S., Wang, C., Ge, J., Fan,
Z., Kong, D., Wang, X. et al. (2017). Macrophages induce AKT/β-catenin-
dependent Lgr5+ stem cell activation and hair follicle regeneration through TNF.
Nat. Commun. 8, 14091. doi:10.1038/ncomms14091
Warren, G. L., Hulderman, T., Mishra, D., Gao, X., Millecchia, L., O’Farrell, L.,
Kuziel, W. A. and Simeonova, P. P. (2005). Chemokine receptor CCR2
involvement in skeletal muscle regeneration. FASEB J. 19, 413-415. doi:10.1096/
fj.04-2421fje
Weisberg, S. P., Mccann, D., Desai, M., Rosenbaum, M., Leibel, R. L. and
Ferrante, A. W. (2003). Obesity is associated with macrophage accumulation in
adipose tissue. J. Clin. Invest. 112, 1796-1808. doi:10.1172/JCI200319246
Winkler, I. G., Sims, N. A., Pettit, A. R., Barbier, V., Nowlan, B., Helwani, F.,
Poulton, I. J., Van Rooijen, N., Alexander, K. A., Raggatt, L. J. et al. (2010).
Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and
their depletion mobilizes HSCs. Blood 116, 4815-4828. doi:10.1182/blood-2009-
11-253534
Wynn, T. A. and Vannella, K. M. (2016). Macrophages in tissue repair, regeneration,
and fibrosis. Immunity 44, 450-462. doi:10.1016/j.immuni.2016.02.015
Yamamoto, R., Wilkinson, A. C. and Nakauchi, H. (2018). Changing concepts in
hematopoietic stem cells. Science 362, 895-896. doi:10.1126/science.aat7873
Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali,
D., Viukov, S., Guilliams, M., Misharin, A. et al. (2013). Fate mapping reveals
origins and dynamics of monocytes and tissue macrophages under homeostasis.
Immunity 38, 79-91. doi:10.1016/j.immuni.2012.12.001
Zheng, C., Yang, Q., Xu, C., Shou, P., Cao, J., Jiang, M., Chen, Q., Cao, G., Han,
Y., Li, F. et al. (2015). CD11b regulates obesity-induced insulin resistance via
limiting alternative activation and proliferation of adipose tissue macrophages.
Proc. Natl. Acad. Sci. USA 112, E7239-E7248. doi:10.1073/pnas.1500396113
Zordan, P., Rigamonti, E., Freudenberg, K., Conti, V., Azzoni, E., Rovere-
Querini, P. and Brunelli, S. (2014). Macrophages commit postnatal endothelium-
derived progenitors to angiogenesis and restrict endothelial to mesenchymal
transition during muscle regeneration. Cell Death Dis. 5, e1031. doi:10.1038/
cddis.2013.558
DEVELOPMENT
14