Inflammatory Bowel Diseases are characterized by disregulated immune responses in the intestine. The mechanisms responsible for the induction of pathogenic T cell responses are still poorly defined, although the recent progress has highlighted the critical roles of commensal bacteria, the innate immune system, myeloid cells (dendritic cells (DC) and macrophages), TH17 cells and regulatory T cells (Tregs). These recent findings have brought up a new focus of investigation, including characterization of the key innate immune signaling pathways and their roles in the development of pathogenic T cell responses. In particular, analyses of TH17 responses in the intestine have elucidated both pathogenic and protective roles of cytokines produced by these cells in the development of colitis. Similarly, accumulating evidence indicates that different innate signaling pathways (for example, IL-23-driven, versus TGFb and IL-6-driven) may have differential roles in the generation of pathogenic versus non-pathogenic or protective Th17 responses. In this proposal, we will investigate the role of innate immune sensing pathways in the initiation of pathogenic T cell responses in the intestine. Specifically, we will investigate the role of IL-6, IL-1, and TGFb in the generation of TH1 and TH17 responses, and their role in development of colitis. We will also examine the role of different innate pathways that lead to the generation of TH17 responses in the intestine.

Public Health Relevance

Our bodies are colonized by trillions of commensal bacteria that normally co-exist peacefully with our immune system. This balance can however be disrupted under certain conditions leading to devastating Inflammatory Bowel Diseases. Multiple mechanisms can contribute to the development of IBD. Initial sensing of intestinal microbiota is mediated by the innate immune system, including Toll like receptors (TLRs). Here we will investigate the role of TLRs and TLR-induced cytokine in the generation of pathogenic T cell responses that are responsible for the development of colitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071754-06
Application #
8296500
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2005-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$360,131
Indirect Cost
$142,631
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ip, W K Eddie; Hoshi, Namiko; Shouval, Dror S et al. (2017) Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356:513-519
Florsheim, Esther; Yu, Shuang; Bragatto, Ivan et al. (2015) Integrated innate mechanisms involved in airway allergic inflammation to the serine protease subtilisin. J Immunol 194:4621-30
Ip, W K Eddie; Medzhitov, Ruslan (2015) Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun 6:6931
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
Kotas, Maya E; Medzhitov, Ruslan (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816-827
Okabe, Yasutaka; Medzhitov, Ruslan (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157:832-44
Chang, Pamela V; Hao, Liming; Offermanns, Stefan et al. (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 111:2247-52
Nish, Simone A; Schenten, Dominik; Wunderlich, F Thomas et al. (2014) T cell-intrinsic role of IL-6 signaling in primary and memory responses. Elife 3:e01949
Palm, Noah W; Medzhitov, Ruslan (2013) Role of the inflammasome in defense against venoms. Proc Natl Acad Sci U S A 110:1809-14
Hoshi, Namiko; Schenten, Dominik; Nish, Simone A et al. (2012) MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nat Commun 3:1120

Showing the most recent 10 out of 17 publications