Endoplasmic reticulum stress and intestinal inflammation

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT Highly secretory intestinal epithelial cells (IEC) are exquisitely sensitive to endoplasmic reticulum (ER) stress and depend upon the unfolded protein response (UPR) to maintain homeostasis and avoid intestinal inflamma- tion and neoplasia. Although a dysregulated IEC-associated UPR can directly cause intestinal inflammation, it is also evident it can orchestrate barrier protective responses. Recently, we discovered that an IEC-associated UPR can induce the generation of T helper 17 (Th17) cells with potentially non-pathogenic properties in a host- intrinsic and microbial independent manner that involves a final common pathway derived from IEC production of xanthine. These UPR-induced Th17 cells are interestingly also marked by expression of GATA3, a canonical marker of Th2 cells. The current research proposal addresses the unanswered question of how an IEC-associ- ated UPR induces a novel population of Th17/Th2 cells and the role played by the intestinal microbiota. Our long-term goals are to unravel the precise mechanisms about the relationship between an IEC-associated UPR and Th17 cells. The objective of this research is to understand how an IEC-associated UPR causes the sterile induction of Th17/Th2 double-positive cells in intestinal tissues and how these are phenotypically and functionally modified by the commensal microbiota and other IEC-associated events. Our central hypothesis is that IEC- associated ER stress is associated with xanthine production and increased differentiation of IECs into Tuft cells which together result in the development of an unusual subset of Th17 cells that co-express GATA3 but whose origin and function in intestines is poorly understood. The rationale for our proposed research is that developing such insights into these mechanisms may allow for the rationale induction of Th17 cells with non-pathogenic and potentially protective activities in intestines. Our central hypothesis will be tested with three specific aims: 1) investigate the function of Th17 cells generated in the setting of uncontrolled ER stress in IECs and the T-cell intrinsic signals required for their induction; 2) identify the signals emanating from the epithelium under ER stress that promote Th17/Th2 development and the regulation of Th17/Th2 cells induced by ER stress in IECs by the microbiota, and; 3) investigate the effect of xanthine, released in response to ER stress by epithelial cells, on host health and its mechanism in supporting Th17 development. In Aim 1, we will determine whether IEC-asso- ciated, UPR-induced Th17 cells are non-pathogenic and if this property is dependent upon GATA3. Aim 2 will show how an ER-stress-induced, Tuft cell expansion and specific commensal microbiota influence the differen- tiation and function of Th17 cells. Aim 3 will ascertain the therapeutic potential of Th17 cell induction by xanthine in intestinal diseases. Overall, this proposal is significant as it will provide new dimensions on our understanding of Th17 cell development, deeper insights into how an IEC-associated, UPR regulates CD4+ T cell differentiation, provide the first identification of Th17/Th2 cells in intestinal tissues and determine if a UPR-derived metabolite can be therapeutically co-opted for potential therapeutic use.