Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation
Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation
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IRAK-M 在调节抗原诱导的气道炎症中的关键作用
DOI：
10.1165/rcmb.2016-0370oc
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发表时间：
2017-11-01
影响因子：
6.4
通讯作者：
Gao, Jinming
中科院分区：
文献类型：
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作者：
Zhang, Mingqiang;Chen, Wei;Gao, Jinming
哮喘是一种呼吸道上皮细胞疾病，涉及过敏性肺部炎症。IL-1受体相关激酶M(IRAK-M)是呼吸道上皮细胞和巨噬细胞上Toll样受体(TLR)信号的负调节因子，可抑制炎症过程中细胞因子的过度产生。然而，IRAK-M在哮喘发病机制中的直接作用尚不清楚。在目前的研究中，我们发现卵蛋白(OVA)暴露后小鼠肺组织中IRAK-M的表达显著增加。与野生型小鼠相比，IRAK基因敲除(KO)小鼠对OVA攻击的反应表现为气道炎性细胞浸润明显加重，气道反应性增强，肺组织匀浆中促炎症细胞因子水平升高，辅助性T细胞2型(Th2)和Th17偏离更明显。卵子暴露还可诱导IRAK-M KO小鼠肺树突状细胞(DC)和巨噬细胞活性升高。此外，将IRAK-M KO骨髓来源的DC或巨噬细胞过继转移到野生型小鼠体内会加重OVA诱导的呼吸道炎症。体外实验表明，IRAK-M KO初始的CD4(+)T细胞更容易分化为Th17细胞，但不能分化为调节性T细胞。一贯地，在没有IRAK-M的情况下，IKB Zeta的激活显著增加，从而促进Th17极化。这些结果表明，IRAK-M通过改变气道上皮细胞、DC和巨噬细胞的功能，以及初始的CD4(+)T细胞的分化，在调节过敏性气道炎症中发挥重要作用。IRAK-M的调节可能为哮喘的控制提供一个新的靶点。
Asthma is an airway epithelium disorder involving allergic lung inflammation. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of Toll-like receptor (TLR) signaling on airway epithelial cells and macrophages, and it is known to limit the overproduction of cytokines during the inflammatory process. However, the direct role of IRAK-M in asthma pathogenesis is unclear. In the present study, we found a significant elevation of IRAK-M expression in mouse lungs after ovalbumin (OVA) exposure. Compared with wild-typemice, IRAK-Mknockout (KO) mice responded to OVA challenge with significantly worse infiltration of airway inflammatory cells, greater airway responsiveness, higher proinflammatory cytokine levels in lung homogenates, and more prominent T-helper cell type 2 (Th2) and Th17 deviation. OVA exposure also induced higher activities of dendritic cells (DCs) and macrophages from IRAK-M KO mouse lungs. Furthermore, adoptive transfer of either IRAK-M KO bonemarrow-derived DCs or macrophages into wild-type mice aggravated OVA-induced airway inflammation. In vitro experiments showed that IRAK-M KO naive CD4(+) T cells were more prone to differentiate into Th17 cells, but not regulatory T cells. Consistently, activation of IkB zeta was significantly increased in the absence of IRAK-M, facilitating Th17 polarization. These findings suggest that IRAK-M plays a crucial role in the regulation of allergic airway inflammation by modifying the function of airway epithelia, DCs, and macrophages, and the differentiation of naive CD4(+) T cells. Modulation of IRAK-M may provide a novel target for the control of asthma.