Date of Award

2010

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Li, Xiaoxia

Subject Headings

Immunology, Natural immunity, Colitis, SIGIRR, Colon epithelium, Th17 cells, mTOR, IL-1R signaling, DSS, Colitis, EAE

Abstract

Single immunoglobulin IL-1R-related receptor (SIGIRR) is a transmembrane protein, which belongs to interleukin 1 receptor (IL-1R)/Toll like receptor (TLR) superfamily (Toll-IL-1R superfamily). SIGIRR has been identified as a negative modulator for IL-1R/TLR signaling. Recently, detailed structural and functional analysis of SIGIRR has been published, however physiological function of SIGIRR has not been studied. To asses the physiological function of SIGIRR, the expression of SIGIRR mRNA in different mouse tissues was analyzed. Although SIGIRR is expressed in many tissues, its expression in different cell types was more restricted, with extremely high expression in primary kidney, colon epithelial cells and T cells, and moderate expression in dendritic cells (DCs). This expression pattern shows a possible regulatory role of SIGIRR in innate and adaptive immune systems. In chapter II, we present in vivo and ex vivo study results showing that SIGIRR in colon epithelial cells plays an important role in the colonic epithelial homeostasis and inflammation by maintaining the microbial tolerance. The colonic epithelium of SIGIRR-deficient mice has increased response to microflora which leads to altered colonic epithelial homeostasis. Moreover, SIGIRR-deficient mice showed hypersensitivity to DSS-induced colitis due to uncontrolled inflammation in the colon, and SIGIRR-deficient mice developed increased tumors in the colon in response to AOM induced tumorigenesis. Interestingly, overexpression of SIGIRR in colon epithelium of SIGIRR-deficient mice normalize some of the defects seen in SIGIRR-deficient mice colonic homeostasis, and reduced the hypersensitivity of SIGIRR-deficient mice to DSS induced colitis and AOM induced tumorigenesis. In chapter III, we also investigated the function of SIGIRR in Th17 cells, a specific T helper cells function in antimicrobial immunity and play a key role in autoimmune diseases. We presented data showing that SIGIRR-deficient mice have increased Experimental Autoimmune Encephalomyeliti

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