REVIEW

CURRENT
OPINION Mouse models of inflammatory bowel disease for
investigating mucosal immunity in the intestine
Giorgos Bamias a, Kristen O. Arseneau b, and Fabio Cominelli b

Purpose of review
Currently several mouse models are considered representative of inflammatory bowel disease (IBD). This
review presents recent developments regarding the role of animal models of intestinal inflammation as
research tools in IBD.
Recent findings
Preclinical studies in animal models of intestinal inflammation have generated novel findings in several
areas of IBD research. The combination of chemical and genetically engineered models have revealed
protective or harmful roles for various components of the innate immune system in response to acute injury
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and repair mechanisms for the intestinal mucosa. Advances in the use of endoscopic and radiologic
techniques have allowed identification of inflammatory biomarkers and in-vivo monitoring of cell trafficking
towards inflammatory sites. Translational research has shed light on pathogenic mechanisms through which
recent biological treatments may exert their beneficial effects in patients with IBD. Finally, novel therapies
are continuously tested in animal models of IBD as part of preclinical drug development programs.
Summary
Animal models of intestinal inflammation continue to be important research tools with high significance for
understanding the pathogenesis of IBD and exploring novel therapeutic options. Development of additional
experimental models that address existing limitations, and more closely resemble the characteristics of
Crohn’s disease and ulcerative colitis are greatly needed.
Keywords
animal models, Crohn’s disease, inflammatory bowel disease, mucosal immunity, ulcerative colitis

INTRODUCTION breakdown during IBD, has been greatly facilitated

The intestinal mucosa is a unique environment in
which an enormous number of gut bacteria and
microbial products that possess immunomodula-
tory properties lie in close proximity to the richest
immunological compartment of the body. As inter-
action between the two is unavoidable, organisms
have developed regulatory mechanisms, known as
mucosal barriers, which supervise host–microbial
immune interactions and maintain a mutually ben-
eficial coexistence. This mucosal immune homeo-
stasis also includes the ability to completely recover
after acute injuries, such as enteric infections, drugs,
toxins, vascular compromise or irradiation. Chronic
intestinal inflammation occurs whenever one or
multiple barrier mechanisms fail under genetic
and/or environmental pressures. The most evident
example of such chronic disruption of mucosal
homeostasis is inflammatory bowel disease (IBD),
which encompasses Crohn’s disease and ulcerative
colitis [1]. Elucidation of immunological pathways
that underlie mucosal homeostasis, as well as their
by the development of animal models of acute and
chronic intestinal inflammation [2]. In this review,
we will summarize the important new findings in
mucosal immunology that have been generated
from studies using mouse models of IBD.
MOUSE MODELS AS RESEARCH TOOLS
Application of experimental findings from mouse
studies to the paradigm for IBD pathogenesis
in humans requires understanding the specific
a
Academic Department of Gastroenterology, Kapodistrian University of
Athens, Laikon Hospital, Athens, Greece and bDivision of Gastrointesti-
nal and Liver Disease, Digestive Health Research Institute, Case Western
Reserve University School of Medicine, Cleveland, Ohio, USA
Correspondence to Giorgos Bamias, MD, PhD, Academic Department of
Gastroenterology, Kapodistrian University of Athens, Laikon Hospital, 17
Agiou Thoma Street, 11527, Athens, Greece. Tel: +30 210 7456504;
fax: +30 210 7791839; e-mail: gbamias@gmail.com
Curr Opin Gastroenterol 2017, 33:411–416
DOI:10.1097/MOG.0000000000000402

0267-1379 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-gastroenterology.com

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Immunology
KEY POINTS
 Animal models of intestinal inflammation are integral to
IBD research.
 Combined use of chemical and genetic models can
elucidate the role of single pathways in the pathobiology
of intestinal homeostasis and inflammation.
 Animal studies allow for better understanding of the
mechanisms of action of novel biological therapies
in IBD.
 Murine models are valuable for evaluation and
application of novel diagnostic techniques and
preclinical drug testing.
advantages and limitations of each mouse model
[3,4]. Based on their mode of generation, animal
models of IBD fall into four categories: chemical
models, genetically engineered models, cell transfer
models, and congenic models. Chemical models use
noxious agents to inflict acute injury to the colon
[5]. As such, they are appropriate for the study of
early repair mechanisms that occur following harm-
ful events that transiently disrupt homeostasis.
However, they have little relevance to the chronic
inflammatory processes that characterizes Crohn’s
disease and ulcerative colitis. Genetically engi-
neered models carry deletions or overexpressions
of specific genes that encode for proteins whose
participation in the pathogenesis of IBD is highly
suspected either through pathogenic hypotheses or
IBD-specific genetic polymorphisms. These models
are pivotal for studying single immune pathways
during homeostasis and inflammation; nonetheless,
they fail to recapitulate the complex, polygenetic
trait representative of the human condition. Cell
transfer models employ injection of donor T-cell
subsets into immunological naı̈ve recipients that
lack adaptive immunity (SCID or RAG mice), and
are used for the study of pathogenic or protective
roles of lymphocytes in mucosal immunity. How-
ever, they employ artificial conditions of immuno-
deficiency that greatly differ from those observed in
IBD. Congenic models develop disease spontane-
ously, as the result of specific breeding, housing,
or genetic backgrounds. Congenic models are the
hardest to develop and maintain in colonies, and
similar to the human condition, have the most
complex and poorly understood underlying immu-
nopathogenesis. These characteristics, however,
make them the most relevant to the human disease.
The fact that vast majority of mouse models of
IBD develop colitis with only few exceptions should
be noted, most notably the ileitis-prone, congenic
SAMP1/Yit(Fc) and genetically engineered TnfDARE/þ
412 www.co-gastroenterology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
models [6,7]. Two additional mouse models of ileitis
were recently described, which are deficient for IBD-
susceptibility genes. Mice lacking myosin IXb
(Myo9b), a motor protein with a Rho GTPase-acti-
vating domain (RhoGAP), were shown to have
impaired intestinal barrier, as indicated by a more
than three-fold decrease in transepithelial electrical
resistance across ileal tissue, loss of tight junction-
associated ZO-1, decreased lateral membrane-asso-
ciated E-cadherin, and loss of terminal web-associ-
&
ated cytokeratin filaments [8 ]. These findings were
associated with clinicopathological evidence of ilei-
tis, including impaired weight gain, positive fecal
occult blood, superficial ulceration, and neutrophil
infiltration. In the second model, mice with epithe-
lial-specific deletion of the autophagy gene, Atg16l1,
developed Crohn’s disease-like transmural ileitis
&&
[9 ] driven by accumulation of the endoplasmic
reticulum stress sensor IRE1a because of defective
autophagy in Paneth cells, which presumably leads
to defective antimicrobial function and dysbiosis.
MOUSE MODELS AS TOOLS FOR
UNRAVELLING PATHOGENIC
MECHANISMS IN INFLAMMATORY
BOWEL DISEASE
Chemical and genetically engineered models are
often used in combination in order to understand
the role of specific molecules in acute response/
repair mechanisms. Recently, dextran sodium sul-
fate (DSS)-induced colitis was induced in mice defi-
cient for wild-type p-53-induced phosphatase 1
(Wip1) [10]. Colitis was more severe in Wip1/
versus wild-type mice, and was associated with
excessive proinflammatory responses, overexpres-
sion of neutrophil-specific markers, and enhanced
migration of neutrophils from the bone marrow of
Wip1/ mice. A similar protective role in DSS colitis
was demonstrated for NADP(þ)-dependent isoci-
trate dehydrogenase (IDH2) [11]. IDH2-deficient
mice suffered from more severe DSS-induced colitis,
an effect that was partially reversed by the adminis-
tration of the antioxidant N-acetylcysteine, which
attenuated the oxidative stress induced by IDH2
deficiency. Deficiency of IDH2 led to p53 up-regu-
lated modulator of apoptosis-mediated apoptosis of
intestinal epithelial cells, indicating that targeting
IDH2 may be of value as a colorectal cancer chemo-
prevention strategy. Pan et al. [12] studied the effect
of myeloid differentiation 1 (MD-1) on the develop-
ment of acute DSS-induced colitis. They showed
that MD-1 mRNA was up-regulated in DSS-treated
wild-type mice, whereas MD-1-deficient mice were
less susceptible to the development of DSS-induced
colitis. This effect was associated with decreased
Volume 33  Number 6  November 2017
 Mouse models as tools to understand mucosal immunity Bamias et al.
numbers of lamina propria dendritic cells, which
also demonstrated decreased maturation and acti-
vation after DSS exposure.
Proteins of the tumor necrosis factor/tumor
necrosis factor receptor superfamilies are important
mediators of clinical and experimental inflamma-
tion. In a recent study, it was shown that mice
deficient for Fn14, the receptor for tumor necrosis
factor-like weak inducer of apoptosis (TWEAK), had
more severe DSS-induced colitis, with higher endo-
scopic and histologic inflammatory scores, increased
weight loss, and higher mortality rates in comparison
&
with wild-type controls [13 ]. Following azoxyme-
thane (AOM) administration, Fn14/ mice showed
enhanced tumorigenesis. Both hematopoietic and
nonhematopoietic components were involved in
intestinal protection. Similarly, mice deficient in
TL1A (TNFSF15) and its receptor DR3 (TNFRSF25)
were more susceptible to DSS-induced colitis in asso-
ciation with their compromised ability to maintain
adequate numbers of CD4þCD25þFoxp3þ Tregs in
&
response to acute mucosal damage [14 ]. Another
study examined the role of Kruppel-like transcription
factor-6 (KLF6) in experimental IBD [15]. In comple-
mentary gain-of-function and loss-of-function stud-
ies, KLF6 was shown to promote NFkB-mediated
proinflammatory gene expression, while simulta-
neously suppressing signal transducer and activator
of transcription 3 (STAT3)-mediated anti-inflamma-
tory gene expression. Myeloid-specific KLF6-knock-
out mice were protected against DSS-induced colitis.
Taken together, these results emphasize the sig-
nificance of innate immune mechanisms in acute
inflammation/repair pathways and indicate their
therapeutic potential in IBD.
MOUSE MODELS AS TOOLS FOR
DEVELOPING NOVEL TECHNIQUES
Recent technical developments have advanced our
ability to examine diverse parameters of intestinal
inflammation in mice with the use of endoscopic and
radiologic techniques, which further potentiate the
applicability of in-vivo preclinical studies in mice to
the study of human IBD [16]. In one such approach,
colon wall thickness was estimated in vivo as a
biomarker of inflammation in mice via magnetic
resonance imaging (MRI) [17]. Sequential MRI meas-
urements detected a significant dose-dependent
increase in colon wall thickness after DSS adminis-
tration and demonstrated excellent correlation with
endoscopic and histological grading of inflamma-
tion severity. Similarly, multispectral optoacoustic
tomography (MSOT) was utilized to detect and grade
the colitis in C57B/6 mice that were treated with
Bacteroides fragilis after antibiotic-mediated depletion
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
of the intestinal flora [18]. MSOT efficiently detected
increases in mesenteric and colonic vascularity, and
mean signal intensity of oxygenated haemoglobin, 2
and 7 days after inoculation. Interestingly, MSOT
demonstrated the development of punctate vascular
lesions on the colonic surface that corresponded with
lesions observed during colonoscopy and through
histological evaluations. These studies indicate the
applicability of noninvasive techniques for longitu-
dinal follow-up of intestinal inflammation in mice,
which may be of particular importance in the study of
small bowel Crohn’s disease.
Other studies have employed advanced imaging
techniques to track immune cells and follow their
recruitment to the inflamed bowel. In one study,
CD25CD45RBhiCD4þ lymphocytes were modified
to express luciferase and then tracked via an in-vivo
imaging system (IVIS) in order to evaluate the devel-
opment of colitis in recipient mice [19]. In compari-
son with clinical markers (weight loss and diarrhea),
IVIS was capable of earlier detection of colitis and
respond to treatment with steroids. IVIS signals cor-
related well with pathological and immunological
results. In a different approach, a chemiluminescent
ROS reporter, coelenterazine, was tested as a tool to
detect immune cell activation both in stimulated
cultured macrophages (RAW 264.7 cell line) as well
as in a mouse model of IBD [20]. The study showed
that this method could detect in vivo, early preclinical
changes in the localization and magnitude of coe-
lenterazine chemiluminescent foci, consistent with
localized immune cell activation. In a final study,
Shin et al. [21] applied in-situ fluorination of inflam-
matory macrophages in the DSS model of colitis to
test whether the magnitude of in-vivo fluorine 19
MRI signal was associated with subsequent develop-
ment of colitis-associated dysplasia induced by con-
comitant administration of azoxymethane. Areas of
(19)F signaling in the colon wall were seen in vivo and
ex vivo and corresponded to sites of chronic inflam-
mation on immunohistochemistry; intensity of the
signaling correlated with the histological severity of
damage. More importantly, sites with increased (19)F
signal intensity localized to areas with dysplasia.
Techniques that examine cell trafficking in vivo
may prove important in monitoring the therapeutic
effects of antiadhesion therapies in IBD.
MOUSE MODELS AS TOOLS FOR
DISSECTING THE MECHANISM OF ACTION
OF ESTABLISHED BIOLOGICAL
THERAPIES FOR INFLAMMATORY BOWEL
DISEASE
There has been a recent expansion in available
biological therapies for patients with IBD. As none
www.co-gastroenterology.com 413
Immunology
of these new biological drugs demonstrate a univer-
sally favorable response, the need arises for individ-
ualized treatment, in which the specifics of the
individual agents should match the unique charac-
teristics of each case [22]. In line with this concept, a
recent study examined the effects of tumor necrosis
factor blockade on the natural history of peptido-
glycan–polysaccharide (PG–PS)-induced Crohn’s
disease-like inflammation and fibrosis in rats
&
[23 ]. The authors observed that antitumor necrosis
factor treatment was effective in reducing both the
median gross abdominal and histologic inflamma-
tion scores whenever given early in the course of
disease, but gradually lost its efficacy whenever
initiated at later time points. This correlated with
major shifts in the mucosal cytokine composition
between early and later time points. Thus, this study
confirmed observations in humans showing
improved outcomes with early introduction of anti-
tumor necrosis factor therapy in Crohn’s disease,
and most probably in ulcerative colitis.
More studies have been published that address
the mechanisms of antitrafficking therapy. These
include agents that block interactions between
a4b7-integrin/mucosal addressing cell-adhesion
molecule-1 (MAdCAM-1) (vedolizumab), a4b7/
MAdCAM-1 and aEb7/E-cadherin (etrolizumab),
and sphingosine-1-phosphate (S1P)/S1P receptor-1
(S1P1) (ozanimob) [24]. One recent study examined
the role of the b7-integrin in recruitment of innate
cells (as opposed to its well established role in lym-
phocytes) [25]. RAG-2-deficient mice also deficient
for b7-integrin (or MAdCAM-1) were treated with
DSS and were protected from the development of
colitis. RAG-2/b7-integrin double-deficient mice
had decreased numbers of colonic effector mono-
cytes but developed colitis whenever adoptively
transferred with CD115þ wild-type monocytes.
Another study identified a novel population of
‘inflammatory’ gd T cells that co-express the gut
homing a4b7 and aE integrins, which may play
an important proinflammatory role in mice with
&&
T-cell-mediated colitis and ileitis [26 ]. Interest-
ingly, detection of these gd T cells preceded the
development of inflammation, whereas upon adop-
tive transfer they induced a Th1/Th17 T-cell gener-
ation and accumulation in the intestine and
increased disease severity. However, a study by Zun-
dler et al. [27] questions the significance of the a4b7/
MAdCAM-1 blockade in prohibiting the movement
of effector T cells to the inflamed bowel, and in
contrast, emphasizes the importance of the a4b1/
VCAM-1 pathway. The authors used a humanized
mouse model to show in vivo that homing of effector
T cells to the ileum was reduced by inhibition of a4
and a4b1 integrins, but not a4b7.
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Recent focus has been placed on targeting the
egress of lymphocytes from the mesenteric lymph
nodes to the systemic circulation via the use of
sphingosine-1-phosphate receptor-1 (S1P1) ago-
nists, such as ozanimob. To gain insight into the
mechanism of action for this biologic, the expres-
sion patterns of S1P1 in mice were examined using
&&
S1P1-eGFP mice [28 ]. The authors assessed S1P1-
bearing populations after induction of colitis by
either DSS or transfer of CD4þCD45RB(hi) cells,
as well as by crossing S1P1-eGFP mice to the ilei-
tis-prone TnfDARE/þ mice. In addition to lympho-
cytes, dendritic cells and endothelial cells also
expressed S1P1, and this was affected by chronic
but not acute inflammatory signals. Furthermore,
the enzymes that control tissue S1P levels were
uniformly dysregulated, favoring synthesis over
degradation. Treatment with FTY720 reduced T-cell
velocity and induced S1P1 degradation and reten-
tion of naı̈ve but not effector T cells. Huang et al.
[29] looked into the role of the two S1P-specific
phosphohydrolase isoforms, SGPP1 and SGPP2,
which catalyze dephosphorylation of S1P to sphin-
gosine. By using isoform-specific knockout mice,
they were able to demonstrate opposing roles of
SGPP1 and SGPP2, in that SGPP1 deletion led to
upregulation of proinflammatory cytokines and
accelerated infiltration of the colon by immune
cells, whereas Sgpp2-null mice failed to mount a
DSS-induced systemic inflammatory response.
They concluded that SGPP2 contributes to the path-
ogenesis of colitis by promoting disruption of the
mucosal barrier function.
Using a different approach, the efficacy of
LCL351, a novel selective inhibitor of sphingosine
kinase 1, which is one of the isozymes that generates
S1P, was tested in mice with DSS-induced colitis
[30]. Treatment with LCL351 ameliorated the sever-
ity of intestinal and systemic inflammation as indi-
cated by decreased blood loss and splenomegaly.
Furthermore, expression of proinflammatory
markers and neutrophil infiltration in the colon
were reduced, raising the possibility for novel ther-
apeutic options in IBD.
Taken together, these studies indicate that sev-
eral trafficking pathways may be involved in the
recruitment of inflammatory cells to the gut and
such diversity may affect the design and efficacy of
antiadhesion therapies.
MOUSE MODELS AS TOOLS FOR TESTING
INVESTIGATIONAL THERAPIES
Animal models constitute an integral part of pre-
clinical drug development programs, as they offer
the opportunity to perform manipulations that
Volume 33  Number 6  November 2017
 Mouse models as tools to understand mucosal immunity Bamias et al.
would be technically impossible or scientifically
unethical in humans. Several recent studies have
tested novel therapeutic approaches for the treat-
ment of intestinal inflammation. In one study,
&&
Popp et al. [31 ] tested the applicability and effi-
cacy of rectal administration of a DNAzyme that
blocks the transcription factor GATA3 (hgd40) in
the chemical models of oxazolone and 2,4,6-trini-
trobenzenesulfonic acid colitis. They found that
mice given hgd40 did not develop chemically
induced colitis, and that they had lower produc-
tion of IL-6, IL-9, and IL-13 by lamina propria cells
and reduced colon inflammation on endoscopy
compared with mice administered a control DNA-
zyme. In another study, investigators used a novel,
antibody-based pharmacodelivery system to create
two fusion proteins that contained IL-22 (IL22-F8),
a cytokine known for its tissue-protective func-
&
tions [32 ]. In mice with DSS-induced colitis,
IL22-F8 accumulated at sites of disease and
induced a more rapid recovery from clinical symp-
toms, as well as improved macroscopic and micro-
scopic morphology of the colon compared with
controls. MacManus et al. [33] used the DSS-
induced colitis and TNFDARE/þ -ileitis models to
test the ability of a recombinant human lactofer-
rin, VEN-120, to regulate T-cell populations. They
found that administration of VEN-120 reduced
inflammation in both models of IBD, and that this
effect was accompanied by increased expression of
regulatory T-cell (Treg) markers and increased
numbers of Tregs in the intestinal lamina propria
because of their enhanced homing to that site. In
another study, investigators tested the therapeutic
potential of substance-P in a mouse model of IBD
[34]. Administration of substance-P to mice led to
inhibition of proinflammatory responses after DSS
administration, by modulating cytokine produc-
tion as well as altering the balance of Tregs/Th 17
cells and the macrophages M1/M2 transition in
lymphoid tissues in favor of anti-inflammatory
pathways, leading to accelerated tissue repair.
Another group looked into the significance of
the resolution of inflammation as a means to limit
& expression induces Crohn’s-like ileitis in mice. PLoS One 2013; 8:e72594.
tissue damage and systemic responses [35 ]. Dur-
ing this process, the roles of resolvin and protectin
pathways appear to be critical. The authors showed
that systemic treatment with protectin (PD)1n-3
DPA or resolvin (Rv)D5n-3 DPA protected against
colitis and intestinal ischemia/reperfusion-
induced inflammation in mice, in association with
decreased leukocyte adhesion and emigration fol-
lowing ischemia–reperfusion. In contrast, inhibi-
tion of 15-lipoxygenase activity reduced PD1n-3
DPA and augmented intestinal inflammation in
experimental colitis.
0267-1379 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
CONCLUSION
Animal models of IBD continue to offer valuable
information on several aspects in IBD research.
They allow the conduct of mechanistic studies that
shed light on the role of single pathways and the
testing of novel therapies at the preclinical level,
and serve as important tools for the application of
novel diagnostic techniques and the search for
biomarkers. Nevertheless, it should be noted that
none of the existing models truly recapitulates the
spontaneous and fluctuating nature of the human
disease. The limitations of each model should
always be taken into consideration before directly
applying experimental findings to the human con-
dition.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Bamias G, Nyce MR, De La Rue SA, Cominelli F. New concepts in the
pathophysiology of inflammatory bowel disease. Ann Intern Med 2005;
143:895–904.
2. Kiesler P, Fuss IJ, Strober W. Experimental models of inflammatory bowel
diseases. Cell Mol Gastroenterol Hepatol 2015; 1:154–170.
3. Valatas V, Bamias G, Kolios G. Experimental colitis models: insights into the
pathogenesis of inflammatory bowel disease and translational issues. Eur J
Pharmacol 2015; 759:253–264.
4. Cominelli F, Arseneau KO, Rodriguez-Palacios A, Pizarro TT. Uncovering
pathogenic mechanisms of inflammatory bowel disease using mouse models
of Crohn’s disease-like ileitis: what is the right model? Cell Mol Gastroenterol
Hepatol 2017; 4:19–32.
5. Wirtz S, Popp V, Kindermann M, et al. Chemically induced mouse models of
acute and chronic intestinal inflammation. Nat Protoc 2017; 12:1295–1309.
6. Pizarro TT, Pastorelli L, Bamias G, et al. SAMP1/YitFc mouse strain: a
spontaneous model of Crohn’s disease-like ileitis. Inflamm Bowel Dis
2011; 17:2566–2584.
7. Bamias G, Dahman MI, Arseneau KO, et al. Intestinal-specific TNFalpha over-
8. Hegan PS, Chandhoke SK, Barone C, et al. Mice lacking myosin IXb, an
& inflammatory bowel disease susceptibility gene, have impaired intestinal
barrier function and superficial ulceration in the ileum. Cytoskeleton (Hobo-
ken) 2016; 73:163–179.
This article reports the development of a novel model of ileitis in mice that lack
myosin IXb, polymorphisms of which have been associated with susceptibility for
developing IBD.
9. Tschurtschenthaler M, Adolph TE, Ashcroft JW, et al. Defective ATG16L1-
mediated removal of IRE1alpha drives Crohn’s disease-like ileitis. J Exp Med
&&
2017; 214:401–422.
A very important work that provides evidence for the functional effects of the
genetic deletion of ATG16L1, which is a Crohn’s disease-susceptibility gene.
10. Zhang Q, Zhang C, Chang F, et al. Wip 1 inhibits intestinal inflammation in
inflammatory bowel disease. Cell Immunol 2016; 310:63–70.
11. Cha H, Lee S, Hwan Kim S, et al. Increased susceptibility of IDH2-
deficient mice to dextran sodium sulfate-induced colitis. Redox Biol
2017; 13:32–38.
www.co-gastroenterology.com 415
Immunology
12. Pan H, Zhang G, Zhang L, et al. MD-1 deficiency attenuates dextran sodium
sulfate (DSS)-induced colitis through modulating the function of colonic
lamina propria dendritic cells. Mol Immunol 2016; 75:1–10.
13. Di Martino L, Dave M, Menghini P, et al. Protective role for TWEAK/Fn14 in
& regulating acute intestinal inflammation and colitis-associated tumorigenesis.
Cancer Res 2016; 76:6533–6542.
This work demonstrates the protective role of TWEAK and its receptor Fn14
against the development of acute intestinal inflammation and colitis-induced
neoplastic transformation.
14. Jia LG, Bamias G, Arseneau KO, et al. A novel role for TL1A/DR3 in protection
& against intestinal injury and infection. J Immunol 2016; 197:377–386.
This study presents unexpected anti-inflammatory roles of the tumor necrosis
factor/tumor necrosis factor receptor proteins TL1A and DR3 during acute DSS-
induced colitis in mice.
15. Goodman WA, Omenetti S, Date D, et al. KLF6 contributes to myeloid cell
plasticity in the pathogenesis of intestinal inflammation. Mucosal Immunol
2016; 9:1250–1262.
16. Rodriguez-Palacios A, Kodani T, Kaydo L, et al. Stereomicroscopic 3D-pattern
profiling of murine and human intestinal inflammation reveals unique structural
phenotypes. Nat Commun 2015; 6:7577.
17. Bianchi A, Bluhmki T, Schonberger T, et al. Noninvasive longitudinal study of a
magnetic resonance imaging biomarker for the quantification of colon inflam-
mation in a mouse model of colitis. Inflamm Bowel Dis 2016; 22:1286–1295.
18. Bhutiani N, Grizzle WE, Galandiuk S, et al. Noninvasive imaging of colitis
using multispectral optoacoustic tomography. J Nucl Med 2017;
58:1009–1012.
19. Chen YL, Chen YT, Lo CF, et al. Early detection of t cell transfer-induced
autoimmune colitis by in vivo imaging system. Sci Rep 2016; 6:35635.
20. Bronsart L, Nguyen L, Habtezion A, Contag C. Reactive oxygen species
imaging in a mouse model of inflammatory bowel disease. Mol Imaging Biol
2016; 18:473–478.
21. Shin SH, Kadayakkara DK, Bulte JW. In vivo 19F MR imaging cell tracking of
inflammatory macrophages and site-specific development of colitis-asso-
ciated dysplasia. Radiology 2017; 282:194–201.
22. Bamias G, Pizarro TT, Cominelli F. Pathway-based approaches to the treat-
ment of inflammatory bowel disease. Transl Res 2016; 167:104–115.
23. Schmiedlin-Ren P, Reingold LJ, Broxson CS, et al. Anti-TNFalpha alters the
& natural history of experimental Crohn’s disease in rats when begun early, but
not late, in disease. Am J Physiol Gastrointest Liver Physiol 2016;
311:G688–G698.
This mechanistic study offers an explanation for the enhanced efficacy of antitumor
necrosis factor agents in patients with early onset/short duration of IBD.
24. Bamias G, Clark DJ, Rivera-Nieves J. Leukocyte traffic blockade as a ther-
apeutic strategy in inflammatory bowel disease. Curr Drug Targets 2013;
14:1490–1500.
25. Schippers A, Muschaweck M, Clahsen T, et al. beta7-Integrin exacerbates
experimental DSS-induced colitis in mice by directing inflammatory mono-
cytes into the colon. Mucosal Immunol 2016; 9:527–538.
416 www.co-gastroenterology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
26. Do JS, Kim S, Keslar K, et al. Min B. gammadelta T cells coexpressing gut
&& homing alpha4beta7 and alphaE integrins define a novel subset promoting
intestinal inflammation. J Immunol 2017; 198:908–915.
Identification of a novel lymphocytic population of gd T cells that express gut
homing integrins and may exert unexpected proinflammatory roles in intestinal
inflammation.
27. Zundler S, Fischer A, Schillinger D, et al. The alpha4beta1 homing pathway is
essential for ileal homing of Crohn’s disease effector T cells in vivo. Inflamm
Bowel Dis 2017; 23:379–391.
28. Karuppuchamy T, Behrens EH, Gonzalez-Cabrera P, et al. Sphingosine-1-
&& phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells,
and endothelium and modulated during inflammatory bowel disease. Mucosal
Immunol 2017; 10:162–171.
Analytical description of the cellular and tissue expression patterns of S1P1, and
its enzymatic regulation during homeostasis and inflammation, which is of im-
portance as this pathway is the target of ozanimob, a novel drug that is being tested
for ulcerative colitis.
29. Huang WC, Liang J, Nagahashi M, et al. Sphingosine-1-phosphate phospha-
tase 2 promotes disruption of mucosal integrity, and contributes to ulcerative
colitis in mice and humans. FASEB J 2016; 30:2945–2958.
30. Pulkoski-Gross MJ, Uys JD, Orr-Gandy KA, et al. Novel sphingosine kinase-1
inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis.
Prostaglandins Other Lipid Mediat 2017; 130:47–56.
31. Popp V, Gerlach K, Mott S, et al. Rectal delivery of a dnazyme that specifically
&& blocks the transcription factor GATA3 and reduces colitis in mice. Gastro-
enterology 2017; 152:176–192.e5.
Proof of principle study that demonstrates the ability of the local delivery of a
DNAzyme to block the Th2-specific trancription factors and supress the severity of
chemical colitis in mice.
32. Bootz F, Ziffels B, Neri D. Antibody-based targeted delivery of interleukin-22
& promotes rapid clinical recovery in mice with DSS-induced colitis. Inflamm
Bowel Dis 2016; 22:2098–2105.
This study presents a novel pharmacological approach to deliver the homeostatic
cytokine IL-22, which exerts anti-inflammatory/pro-resolution effects after acute
intestinal injury in mice.
33. MacManus CF, Collins CB, Nguyen TT, et al. VEN-120 a recombinant human
lactoferrin, promotes a regulatory T cell (Treg) phenotype and drives resolu-
tion of inflammation in distinct murine models of inflammatory bowel disease. J
Crohns Colitis 2017; 11:1113–1123.
34. Hong HS, Hwang DY, Park JH, et al. Substance-P alleviates dextran sulfate
sodium-induced intestinal damage by suppressing inflammation through en-
richment of M2 macrophages and regulatory T cells. Cytokine 2017; 90:21–30.
35. Gobbetti T, Dalli J, Colas RA, et al. Protectin D1n-3 DPA and resolvin D5n-3
& DPA are effectors of intestinal protection. Proc Natl Acad Sci USA 2017;
114:3963–3968.
This study emphasizes the role of the resolution of inflammation in mucosal home-
ostasis and demonstrates that during this process, resolvin and protectin pathways
may be effectively manipulated to protect from systemic immune responses.
Volume 33  Number 6  November 2017