Ablation of IL-17A leads to severe colitis in IL-10-deficient mice: implications of myeloid-derived suppressor cells and NO production.,International Immunology

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Ablation of IL-17A leads to severe colitis in IL-10-deficient mice: implications of myeloid-derived suppressor cells and NO production.
International Immunology ( IF 4.8 ) Pub Date : 2020-03-07 , DOI: 10.1093/intimm/dxz076
Masashi Tachibana _{1,

2,

3} , Nobumasa Watanabe ₄ , Yuzo Koda ₁ , Yukako Oya ₁ , Osamu Kaminuma ₄ , Kazufumi Katayama ₁ , Zifei Fan ₁ , Fuminori Sakurai ₁ , Kenji Kawabata ₅ , Takachika Hiroi ₄ , Hiroyuki Mizuguchi _{1,

3,

6,

7}

Affiliation

IL-10 is an immune regulatory cytokine and its genetic defect leads to gastrointestinal inflammation in humans and mice. Moreover, the IL-23/Th17 axis is known to be involved in these inflammatory disorders. IL-17A, a representative cytokine produced by Th17 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.

中文翻译：

IL-17A的消融会导致IL-10缺陷小鼠严重结肠炎：髓样抑制细胞和NO产生的影响。

IL-10是一种免疫调节细胞因子，其遗传缺陷会导致人类和小鼠的胃肠道炎症。此外，已知IL-23 / Th17轴参与这些炎性疾病。IL-17A是Th17细胞产生的代表性细胞因子，在炎症性疾病的病理过程中具有重要作用。但是，IL-17A在炎症性肠病（IBD）中的确切功能仍存在争议。在这项研究中，我们评估了IL-17A对IL-10缺乏（Il10-/-）小鼠结肠炎的影响。与Il10-/-Il17a +/-小鼠相比，缺乏IL-10和IL-17A（Il10-/-Il17a-/-）的小鼠遭受致命性消耗，表现出更严重的结肠炎。此外，我们发现CD11b + Gr-1 +髓样抑制细胞（MDSCs）积累在Il10-/-Il17a-/-小鼠的骨髓，脾脏和外周血中。这些MDSCs高度表达诱导型一氧化氮合酶（iNOS）（Nos2），并以NOS依赖性方式在体外抑制T细胞应答。与这些作用相关，II10-/-Il17a-/-小鼠的血清中一氧化氮的浓度升高。令人惊讶地，在Il10-/-Il17a-//-小鼠中观察到的严重结肠炎得到改善。我们的发现表明，IL-17A以iNOS依赖的方式对Il10-/-小鼠中的自发性结肠炎起抑制作用，并抑制MDSC分化和/或增殖。在Il10-/-Il17a-/-小鼠中观察到的严重结肠炎得到改善。我们的发现表明，IL-17A以iNOS依赖的方式对Il10-/-小鼠中的自发性结肠炎起抑制作用，并抑制MDSC分化和/或增殖。在Il10-/-Il17a-/-小鼠中观察到的严重结肠炎得到改善。我们的发现表明，IL-17A以iNOS依赖的方式对Il10-/-小鼠中的自发性结肠炎起抑制作用，并抑制MDSC分化和/或增殖。

更新日期：2019-11-01

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