Interleukin-17 Induces an Atypical M2-Like Macrophage Subpopulation That Regulates Intestinal Inflammation

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.

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

“…To further confirm that the function of Fbxw7 in colitis was dependent on macrophages, we depleted macrophages using clodronate-containing liposomes (CLs) (26,27). Flow cytometric analysis confirmed a marked reduction in the percentages of local macrophages in mice treated with CLs (Supplemental Figure 7, A and B).…”

5‐HT3 receptors promote colonic inflammation via activation of substance P/neurokinin‐1 receptors in dextran sulphate sodium‐induced murine colitis

“…The expression of TNF‐α and iNOS mRNA was further augmented on day 10, while that of IFN‐γ and IL‐17A mRNA was reduced at this time point. A similar time course of cytokine expression was identified by Nishikawa et al () in DSS‐induced colitis. IFN‐γ and IL‐17 may therefore act as regulatory cytokines, inducing production of downstream pro‐inflammatory cytokines, chemokines and iNOS‐derived NO.…”

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

“…Emerging evidence, however, supports the notion that IL-17A may play a protective role in tissue repair and inflammation (Gopal et al, 2014; Littman and Rudensky, 2010; Nascimento et al, 2015; Nishikawa et al, 2014; O'Connor, Jr. et al, 2009). Likewise, studies in MS and EAE led to conflicting results on the role of IL-17A in disease development (Haak et al, 2009; Harrington et al, 2005; Hu et al, 2010; Komiyama et al, 2006; Luchtman et al, 2014; Niimi et al, 2013).…”