Abstract
Myeloid-derived suppressor cells (MDSC) play a crucial role in regulating the intestinal immune response during colitis. We previously revealed an essential role of MDSC in promoting TH17 cell polarization, which was found to be arginase-1 (Arg-1)-dependent; however, the underlying mechanism remains obscure. Here we report that percentage of MDSC decreased in ArgmyeKO mice during DSS-induced colitis. IL-17A levels reduced but IL-17F levels increased significantly in the colorectum of ArgmyeKO mice, leading to severe tissue damage and high risk of mortality rate. Activation of estrogen receptor (ESR) increased pSTAT3 level in MDSC and consequently led to elevated percentage of MDSC and more Arg-1 and inducible nitric oxide synthase expression in MDSC. Increased level of IL-17A and reduced level of IL-17F alleviated colitis in mice consequently. Together, these findings demonstrate a protective role of MDSC-derived Arg-1 during colitis after activates ESR/STAT3 signaling in MDSC. High level of Arg-1 favors accumulation of IL-17A, but reduced IL-17F expression in the colorectum of mice and ultimately leading to relief of colitis, indicating a potential clinical impact of MDSC-derived Arg-1 for controlling inflammatory bowel disease.
Highlights
Inflammatory bowel disease (IBD) is a chronic and relapsing disorder that involves the whole intestinal system, and generally indicates ulcerative colitis (UC) and Crohn’s Disease (CD) in human
IL17F production by TH17 cells was decreased in the mesenteric lymph nodes (mLN), but not in the Peyer’s patches (PP) (Figures 8D,F), which is in line with a report that lower IL-17F level alleviates dextran sodium sulfate (DSS)-induced colitis in mice [11]. γδT cells are another main source of IL-17A, we found that the population of γδT cells in the PP was reduced after quercetin treatment (Figure 8G)
We demonstrated that Arg-1 deletion in myeloid cells promoted DSS-induced colitis progression via decreases in the Myeloid-derived suppressor cells (MDSC) and TH17 cell populations
Summary
Inflammatory bowel disease (IBD) is a chronic and relapsing disorder that involves the whole intestinal system, and generally indicates ulcerative colitis (UC) and Crohn’s Disease (CD) in human. When the epithelial barrier is broken, microbial antigens and self-antigens are processed and presented by antigen-presenting cells, which elicit fierce pro-inflammatory activity after activation, recruiting various immune cells to the inflammatory sites and attacking intestinal cells [3,4,5]. Both innate and adaptive immune cells participate in IBD progression by secreting various cytokines [6].
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