Ablation of IL-17A leads to severe colitis in IL-10-deficient mice: implications of myeloid-derived suppressor cells and NO production. (22nd November 2019)

• Record Type: Journal Article
• Authors: Tachibana, Masashi; Watanabe, Nobumasa; Koda, Yuzo; Oya, Yukako; Kaminuma, Osamu; Katayama, Kazufumi; Fan, Zifei; Sakurai, Fuminori; Kawabata, Kenji; Hiroi, Takachika; Mizuguchi, Hiroyuki
• Is Part Of: International immunology. Volume 32:Number 3(2020)
• Page Start: 187
• Page End: 201
• Publication Date: 2019-11-22
• Subjects: colitis -- IL-17A -- MDSC -- nitric oxide; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxz076
• Languages: English
• ISSNs: 0953-8178

Abstract

Abstract: IL-10 is an immune regulatory cytokine and its genetic defect leads to gastrointestinal inflammation in humans and mice. Moreover, the IL-23/Th 17 axis is known to be involved in these inflammatory disorders. IL-17A, a representative cytokine produced by Th 17 cells, has an important role for the pathological process of inflammatory diseases. However, the precise function of IL-17A in inflammatory bowel disease (IBD) remains controversial. In this study, we evaluated the effect of IL-17A on colitis in IL-10-deficient ( Il10 −/− ) mice. Mice lacking both IL-10 and IL-17A ( Il10 −/− Il17a −/− ) suffered from fatal wasting and manifested more severe colitis compared with Il10 −/− Il17a +/− mice. Moreover, we found that CD11b + Gr-1 + myeloid-derived suppressor cells (MDSCs) accumulated in the bone marrow, spleen and peripheral blood of Il10 −/− Il17a −/− mice. These MDSCs highly expressed inducible nitric oxide synthase (iNOS) ( Nos2 ) and suppressed the T-cell response in vitro in a NOS-dependent manner. In correlation with these effects, the concentration of nitric oxide was elevated in the serum of Il10 −/− Il17a −/− mice. Surprisingly, the severe colitis observed in Il10 −/− Il17a −/− mice was ameliorated in Il10 −/− Il17a −/− Nos2 −/− mice. Our findings suggest that IL-17A plays suppressive roles against spontaneous colitis in Il10 −/− mice in an iNOS-dependent manner and inhibits MDSC differentiation and/or proliferation. Abstract : NO exacerbates colitis in mice lacking IL-10 and IL-17A