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Zhang, Ada Yu-Jie

University of British Columbia

Inflammatory bowel disease (IBD) is characterized by inflammation along the gastrointestinal tract, which may develop from disruptions in mucosal homeostasis. Intestinal epithelial cells are central in maintaining homeostasis by recognizing and responding to extracellular signals. One of these cell types, tuft cells, has been proposed to have a role in secretion, absorption, and/or reception. However, their role in the intestine remains understudied. We found that tuft cells express SH2 domain-containing inositol 5'-phosphatase (SHIP), which is thought to be hematopoietic-specific. SHIP is a negative regulator of the PI3-kinase pathway, so SHIP deficiency increases PI3K-mediated cell growth, proliferation, and activation. Tuft cells secrete IL-25, which activates group 2 innate lymphoid cells (ILC2s), inducing type 2 immune responses that can promote inflammation and tissue repair. Tuft cells also express cyclooxygenase (COX)1 and COX2, which produce prostaglandins that regulate inflammation and repair. I hypothesized that SHIP deficiency in tuft cells increases their activity, promoting inflammation and/or healing via activation of type 2 immunity and prostaglandin synthesis. We created a mouse deficient in SHIP only in intestinal tuft cells to examine tuft cell functions in DSS-induced colitis, a mouse model of colonic inflammation. I found that mice with SHIP-deficient tuft cells have exacerbated DSS-induced colitis that is accompanied by elevated IL-25 concentrations and reduced COX activity. IL-5 and IL-13 concentrations were not increased, suggesting that these type 2 cytokines did not worsen disease and the tuft cell-ILC2 circuit may not function in the colon. Pro-inflammatory mediators, eosinophils, IL-1β, IL-6, and TNF-α, did not appear to exacerbate disease. Rather, my results suggest that endogenous IL-25 plays a pro-inflammatory role, whereas COX is protective in DSS-induced colitis. I evaluated the potential protective function of COX during recovery from DSS-induced colitis. I found that mice with SHIP-deficient tuft cells have increased disease activity early in recovery and may have some histological features that are consistent with increased type 2-mediated healing. Investigating the role of tuft cell-derived IL-25 and COX in DSS-induced colitis and recovery may provide insight into the biological processes that occur in the development of intestinal inflammation that is pertinent to IBD.  

Text

2021-07-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79010

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/