Inflammatory immune responses at mucosal surfaces are critical for protection against invading microbial pathogens. However, when these are inappropriately targeted against commensal flora or food proteins, the resulting inflammation is detrimental to the host. Inflammatory Bowel Disease (IBD) is a chronic, relapsing and remitting immune-mediated inflammatory disorder without a cure or uniformly effective treatments. Genetics, intestinal flora, and immune regulation all play important roles in the pathogenesis of IBD, yet the precise etiology remains unknown. The Interleukin 23 (IL23) receptor is associated with susceptibility to IBD. IL23 acts on key cellular players in IBD: CD4+ T cells of the Th17 and Th22 subsets, as well as the recently-identified Group 3 Innate Lymphoid Cells (ILC3s). Together, these cells orchestrate an immune response typified by production of cytokines (IL17 and IL22), that act on epithelial cells to drive production of antimicrobial peptides, chemokines and cytokines that recruit immune cells to the lamina propria. These same inflammatory responses are required for clearance Citrobacter rodentium infection in mice. In the C rodentium model, pathogen control comes at the cost of developing transient colitis that bears many features of IBD. Our previous studies have indicated an important role for IL23 dependent integrin expression on inflammatory Th17 cells in autoimmunity. Additionally, integrin specific ligands are associated with IBD. The goal of this proposal is to determine the role of IL23 driven integrins in mucosal inflammation elicited by C rodentium. Our preliminary data indicate that both T cells and ILCs express integrins during C rodentium infection, and expression is particularly high on IL22-producing cells. IL22-producing cells are known to be critical for infection control. These data lead to our central hypothesis that IL23 driven integrins promote the inflammatory functions of both innate and adaptive inflammatory immune cell populations in the gut.
The aims of the proposed project are: 1) Determine the role of integrins in the adaptive immune response to C. rodentium colitis, and 2) Define the early function of integrins on intestinal ILCs in infectious colitis. Collectively, these experiments will define the requirements and functions of integrin expression during the inflammatory response to C rodentium in the gut. Integrins are being targeted therapeutically, and therefore these studies will define and validate the potential of additional integrins as therapeutic candidates for IBD.

Public Health Relevance

Inflammatory Bowel Disease (IBD) is an intestinal inflammatory disorder without a cure. The environment and infection play important roles in IBD, but the cause of disease remains unknown;therefore, there is a need to understand how infection influences the intestinal immune system. The studies proposed in this application will help us determine the function of molecules present on immune cells in the intestine, which is important for the development of new treatments for IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DK104554-01
Application #
8835817
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Podskalny, Judith M,
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213