Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis
Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis
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DOI：
10.4049/jimmunol.1601982
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发表时间：
2017-08-15
影响因子：
4.4
通讯作者：
Lech, Maciej
中科院分区：
文献类型：
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作者：
Steiger, Stefanie;Kumar, Santhosh V.;Lech, Maciej
各种先天性免疫受体的激活导致IL-1受体相关激酶（IRAK）-1/IRAK-4介导的信号传导和促炎细胞因子如IL-12、IL-6或TNF-α的分泌，所有这些都与组织损伤有关并在组织重塑过程中升高。IRAK-M，也称为IRAK-3，是肾内巨噬细胞中促炎细胞因子和趋化因子表达的抑制剂。先天性免疫激活有助于急性肾损伤和与慢性肾病（CKD）相关的组织重塑。我们的研究评估了巨噬细胞在CKD中的作用以及IRAK-M在调节疾病进展中的作用。为了评价IRAK-M在体内慢性肾损伤中的作用，采用单侧输尿管梗阻（UUO）的小鼠模型。梗阻组IRAK-M表达在术后2d内较通畅组增加。IRAK-M缺陷的小鼠免受纤维化的影响，并显示出数量减少的交替活化的巨噬细胞。与野生型小鼠相比，IRAK-M缺陷型小鼠表现出肾损伤后肾小管损伤、白细胞浸润和炎症减少，如通过光学显微镜、免疫组织化学和肾内促炎和促纤维化介质的mRNA表达所确定的。总之，这些结果强烈支持IRAK-M在肾损伤中的作用，并将IRAK-M鉴定为在UUO诱导的CKD中驱动替代活化的促纤维化巨噬细胞表型的可能调节剂。
Activation of various innate immune receptors results in IL-1 receptor-associated kinase (IRAK)-1/IRAK-4-mediated signaling and secretion of proinflammatory cytokines such as IL-12, IL-6, or TNF-alpha, all of which are implicated in tissue injury and elevated during tissue remodeling processes. IRAK-M, also known as IRAK-3, is an inhibitor of proinflammatory cytokine and chemokine expression in intrarenal macrophages. Innate immune activation contributes to both acute kidney injury and tissue remodeling that is associated with chronic kidney disease (CKD). Our study assessed the contribution of macrophages in CKD and the role of IRAK-M in modulating disease progression. To evaluate the effect of IRAK-M in chronic renal injury in vivo, a mouse model of unilateral ureteral obstruction (UUO) was employed. The expression of IRAK-M increased within 2 d after UUO in obstructed compared with unobstructed kidneys. Mice deficient in IRAK-M were protected from fibrosis and displayed a diminished number of alternatively activated macrophages. Compared to wild-type mice, IRAK-M-deficient mice showed reduced tubular injury, leukocyte infiltration, and inflammation following renal injury as determined by light microscopy, immunohistochemistry, and intrarenal mRNA expression of proinflammatory and profibrotic mediators. Taken together, these results strongly support a role for IRAK-M in renal injury and identify IRAK-M as a possible modulator in driving an alternatively activated profibrotic macrophage phenotype in UUO-induced CKD.