Abstract
Interleukin 17 (IL-17) is a pleiotropic cytokine that acts on both immune and non-immune cells and is generally implicated in inflammatory and autoimmune diseases. Although IL-17 as well as their source, mainly but not limited to Th17 cells, is also abundant in the inflamed intestine, the role of IL-17 in inflammatory bowel disease remains controversial. In the present study, by using IL-17 knockout (KO) mice, we investigated the role of IL-17 in colitis, with special focus on the macrophage subpopulations. Here we show that IL-17KO mice had increased susceptibility to DSS-induced colitis which was associated with decrease in expression of mRNAs implicated in M2 and/or wound healing macrophages, such as IL-10, IL-1 receptor antagonist, arginase 1, cyclooxygenase 2, and indoleamine 2,3-dioxygenase. Lamina propria leukocytes from inflamed colon of IL-17KO mice contained fewer CD11b+Ly6C+MHC Class II+ macrophages, which were derived, at least partly, from blood monocytes, as compared to those of WT mice. FACS-purified CD11b+ cells from WT mice, which were more abundant in Ly6C+MHC Class II+ cells, expressed increased levels of genes associated M2/wound healing macrophages and also M1/proinflammatory macrophages. Depletion of this population by topical administration of clodronate-liposome in the colon of WT mice resulted in the exacerbation of colitis. These results demonstrate that IL-17 confers protection against the development of severe colitis through the induction of an atypical M2-like macrophage subpopulation. Our findings reveal a previously unappreciated mechanism by which IL-17 exerts a protective function in colitis.
Highlights
Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) is a chronic inflammatory disease with recurring relapses and remissions in the lower gastrointestinal tract [1,2]
To reassess the role of Interleukin 17 (IL-17) in dextran sulfate sodium (DSS)-induced colitis, we administered 1.5% DSS in drinking water to age- and sexmatched IL-17KO and WT mice for 7 days followed by water consumption alone with untreated mice serving as controls
CD11b+ cells in the inflamed colonic lamina propria leukocytes (LPLs) of WT mice express signature transcription factors and their target genes implicated in anti-inflammatory M2/wound healing macrophages To gain insight into the unique features of macrophages that emerged in the inflamed colons of WT that seem to have regulatory function for colitis, we looked into genes expressed in CD11b+ cells, more abundant in Ly6C+MHC Class II+ cell in LP of colitic WT mice as compared to those from IL-17KO mice
Summary
Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) is a chronic inflammatory disease with recurring relapses and remissions in the lower gastrointestinal tract [1,2]. IL-17 as well as their source, mainly but not limited to Th17 cells, is found in the inflamed intestine in both animal models and humans [4,5], but the role of IL-17 in IBD remains controversial [6,7]. In models of both acute and chronic intestinal inflammation where mice were administered with trinitrobenzene sulfonic acid or infected with Helicobacter hepaticus, respectively, IL-17 showed a pathogenic role [8,9]. In a dextran sulfate sodium (DSS)-induced colitis model, IL-17 has been shown to exert pro- [12] and anti-[13,14] colitogenic activities, adding an additional layer of complexity
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