The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards commensal microbiota are believed to underlie disease pathogenesis. We have demonstrated that the intestinal lamina propria (LP) antigen presenting cell network is incredibly complex with several subsets of macrophages and dendritic cells (DCs) that differ phenotypically, functionally, and regionally along the length of the mouse intestine during homeostasis and inflammation. Our investigations revealed that steady state CX3CR1-expressing LP macrophages are major producers of IL-10 and are adept at promoting Foxp3+ Treg cell differentiation in an IL-10- and retinoic acid-dependent manner. Conversely, we discovered that CD103-expressing LP DCs are poor producers of IL-10 and the CD11b+ LP DC subset expresses TGF? and IL-6 and drives the differentiation of Th17 cells both in vitro and in vivo. More recently, we made the novel observation that the CX3CR1/CX3CL1 axis is critically important for maintaining LP macrophage homeostasis, bacterial translocation, and limiting colitogenic Th17 responses. In the course of these studies we discovered that CX3CR1 deficiency leads to a loss of resident LP macrophages in the steady state, however during colitis the LP is populated by a unique subset of Ly6C-expressing inflammatory macrophages. With the knowledge that CX3CR1-expressing anti-inflammatory LP macrophages are abundant in the healthy intestine, while Ly6C-expressing pro-inflammatory LP macrophages dominate the inflamed intestine, we performed a DNA microarray analysis of these two subsets in order to identify candidate genes that may be targeted for therapeutic purposes. As a result of the microarray comparison, we identified the novel IL-1 family member IL-36? as the top most preferentially expressed cytokine in Ly6C+ LP macrophages. Several members of the IL-1 family of cytokines, including IL-1?, IL-1?, IL-18 and IL-33 are associated with the pathogenesis of experimental and human IBD, however the expression and function of IL-36? in the intestine is completely unexplored. Our exciting preliminary data demonstrate that IL-36? promotes LP macrophage and DC activation and that blocking of IL-36R during colitis ameliorates disease. In this proposal we will specifically determine the role of IL-36 ligands in modulating innate and adaptive immune responses during intestinal inflammation. The outcome of these studies will have potential therapeutic value for treating human IBD.

Public Health Relevance

The present first-time application will focus on defining the role of novel IL-36 ligands (IL-36?, IL-36?, IL-36?) in the pathogenesis of experimental inflammatory bowel disease (IBD). The proposal will test the novel hypothesis that inhibition of IL-36?/IL-36R signaling limits immune activation and intestinal inflammation associated with mouse models of IBD. New mechanistic insights defining the role of IL-36 ligands in modulating innate and adaptive immune responses during intestinal inflammation will have potential therapeutic value for treating human IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Perrin, Peter J
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Georgia State University
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United States
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Ngo, Vu L; Abo, Hirohito; Maxim, Estera et al. (2018) A cytokine network involving IL-36?, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage. Proc Natl Acad Sci U S A 115:E5076-E5085
Flannigan, Kyle L; Denning, Timothy L (2018) Segmented filamentous bacteria-induced immune responses: a balancing act between host protection and autoimmunity. Immunology :
Pujada, Adani; Walter, Lewins; Patel, Aashka et al. (2017) Matrix metalloproteinase MMP9 maintains epithelial barrier function and preserves mucosal lining in colitis associated cancer. Oncotarget 8:94650-94665
Harusato, A; Abo, H; Ngo, V L et al. (2017) IL-36? signaling controls the induced regulatory T cell-Th9 cell balance via NF?B activation and STAT transcription factors. Mucosal Immunol 10:1455-1467
Denning, Timothy L; Bhatia, Amina M; Kane, Andrea F et al. (2017) Pathogenesis of NEC: Role of the innate and adaptive immune response. Semin Perinatol 41:15-28
Quiros, Miguel; Nishio, Hikaru; Neumann, Philipp A et al. (2017) Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Invest 127:3510-3520
Flannigan, K L; Ngo, V L; Geem, D et al. (2017) IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal Immunol 10:673-684
Harusato, Akihito; Geem, Duke; Denning, Timothy L (2016) Macrophage Isolation from the Mouse Small and Large Intestine. Methods Mol Biol 1422:171-80
Medina-Contreras, Oscar; Harusato, Akihito; Nishio, Hikaru et al. (2016) Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage. J Immunol 196:34-8
Geem, Duke; Ngo, Vu; Harusato, Akihito et al. (2016) Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell Compartment. Cell Mol Gastroenterol Hepatol 2:274-280

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