Intestinal mucosal surfaces are protected by a first-line defense mediated by secretory IgA (SIgA). That IgA plays a key role in gut homeostasis is strongly suggested by the observations that in patients with severe IgA deficiency (SlgAD) or common variable immunodeficiency (CVID), impaired IgA production triggers persistent symptoms including gastrointestinal infections. Development of intestinal inflammation and small intestinal nodular lesions is often seen in IgA-deficient patients, a phenomenon attributed to aberrant expansion of commensal bacteria. Multiple signals, including T cell-dependent and -independent pathways, regulate IgA induction. However, the relative importance of each and how they are regulated remain poorly understood. Yet, a better understanding of the IgA response is key to understanding intestinal immune homeostasis and the pathogenesis of inflammatory bowel disease (IBD). Th17 cells, which produce IL-17 (IL-17A), IL-17F, IL-21 and IL-22, have recently been shown to be important in the maintenance of immune homeostasis, in addition to their pro-inflammatory function. Although high amounts of IgA and Th17 cells are both present constitutively in the intestine, there are sparse data that address how each of these systems respond to antigens of the microbiota, or whether these two systems interact in that effort, in regulation of host response to microbiota and the pathogenesis of IBD. In this project, we will investigate how Th17 cells promote intestinal IgA production, and whether Th17 cells regulate the differentiation and maintenance of memory IgA+ B cells. Finally, we will test our hypothesis that in context with intestinal IgA, Th17 cells regulate commensal bacteria colonization and translocation and thus contribute to intestinal homeostasis and protect the intestine from inflammation in response to microbiota. Under the conditions of an impaired intestinal IgA response, disregulated Th17 cells are proinflammatory and able to induce colitis. Upon completion, the proposed studies will establish a novel pathway of Th17 cells through induction of an intestinal IgA response in the regulation of intestinal immune homeostasis and protection of the intestines from inflammation in response to microbiota, as well as the pathogenesis of inflammatory bowel diseases.
Inflammatory bowel diseases (IBD) are diseases of immune dysregulation and a subset of lymphocytes, namely T helper-17 (Th17) cells, play a role in the pathogenesis of IBD. However, our recent studies indicated that Th17 cells also protect the intestines from inflammation. Intestines contain abundant antibody isotype IgA, which plays the first line of defense in the intestine against bacteria in the gut. This proposal will address whether and how Th17 cells promote intestinal IgA production to protect the intestines from inflammation and what does it mean to IBD pathogenesis, a finding that would allow us to identify the potential pathways that can lead to development of a successful therapy for established IBD.
|Sun, Mingming; Wu, Wei; Chen, Liang et al. (2018) Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun 9:3555|
|Chen, Feidi; Yang, Wenjing; Huang, Xiangsheng et al. (2018) Neutrophils Promote Amphiregulin Production in Intestinal Epithelial Cells through TGF-? and Contribute to Intestinal Homeostasis. J Immunol 201:2492-2501|
|Zhong, Xiaoying S; Winston, John H; Luo, Xiuju et al. (2018) Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life. Cell Mol Gastroenterol Hepatol 6:65-78|
|Zhao, Ye; Chen, Feidi; Wu, Wei et al. (2018) GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 11:752-762|
|Wu, W; Sun, M; Chen, F et al. (2017) Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol 10:946-956|
|Sun, Mingming; Wu, Wei; Liu, Zhanju et al. (2017) Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J Gastroenterol 52:1-8|
|Liu, Han; Chen, Feidi; Wu, Wei et al. (2016) TLR5 mediates CD172?(+) intestinal lamina propria dendritic cell induction of Th17 cells. Sci Rep 6:22040|
|Chen, Feidi; Cao, Anthony; Yao, Suxia et al. (2016) mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production. J Immunol 196:4390-9|
|Wu, Wei; Liu, Hou-Pu; Chen, Feidi et al. (2016) Commensal A4 bacteria inhibit intestinal Th2-cell responses through induction of dendritic cell TGF-? production. Eur J Immunol 46:1162-7|
|Wu, Wei; Chen, Feidi; Liu, Zhanju et al. (2016) Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease. Inflamm Bowel Dis 22:1473-82|