Critical Role of Alternative M2 Skewing in miR-155 Deletion-Mediated Protection of Colitis.
Critical Role of Alternative M2 Skewing in miR-155 Deletion-Mediated Protection of Colitis.
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DOI：
10.3389/fimmu.2018.00904
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Li J;Zhang J;Guo H;Yang S;Fan W;Ye N;Tian Z;Yu T;Ai G;Shen Z;He H;Yan P;Lin H;Luo X;Li H;Wu Y
炎症性肠病（IBD）与肠道先天性和适应性免疫反应失调有关。 MicroRNA (miR)-155 在许多免疫细胞类型中频繁表达并发挥作用。除了在适应性免疫中的功能外，miR-155 也是巨噬细胞、树突状细胞甚至上皮细胞先天免疫反应的关键调节因子。尽管 miR-155 在结肠炎中 T 和 B 淋巴细胞中的作用已被报道，但其在先天免疫细胞中的功能尚未得到彻底检查。在本研究中，在野生型（WT）和miR-155−/−小鼠中建立了葡聚糖硫酸钠（DSS）诱导的结肠炎模型。我们的结果表明，巨噬细胞中的 miR-155 缺陷再现了 miR-155−/− 小鼠结肠炎减轻的特征，并且似乎倾向于替代 M2 表型。值得注意的是，M2 在结肠中的优势可导致肠道免疫细胞增殖抑制，并抑制 CD4 T 细胞向 Th1 和 Th17 极化。此外，C/EBPβ和SOCS1被证明是该过程中的两个关键功能靶点。我们还提供了使用 miR-155 抑制剂治疗结肠炎的证据。总的来说，这些发现强调了结肠炎中 miR-155 功能的替代 M2 偏斜的核心作用，并揭示巨噬细胞可能是治疗的主要靶点。
Inflammatory bowel disease (IBD) is associated with dysregulation of both innate and adaptive immune response in the intestine. MicroRNA (miR)-155 is frequently expressed and functions in many immune cell types. Besides its function in adaptive immunity, miR-155 is a key regulator of the innate immune response in macrophages, dendritic cells, and even in epithelia cells. Although the roles of miR-155 within T and B lymphocytes in colitis have been reported, its function in innate immune cells has not been thoroughly examined. In this study, the dextran sulfate sodium (DSS)-induced colitis model was established in wild-type (WT) and miR-155−/− mice. Our results showed that miR-155 deficiency in macrophages recapitulated the alleviated colitis feature of miR-155−/− mice and appeared to skew toward the alterative M2 phenotype. Notably, the predominance of M2 in colon can result in dampened intestinal immune cell proliferation and inhibit CD4 T cell polarization toward Th1 and Th17. Moreover, C/EBPβ and SOCS1 were demonstrated as two key functional targets in this process. We also provided evidence for use of miR-155 inhibitor to treat colitis. Collectively, the findings highlight the central role of alternative M2 skewing for miR-155 function in colitis and reveal that macrophages might be a main target for therapeutics.