Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE)
Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE)
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白细胞介素1受体相关激酶（IRAK）-M介导的2型小胶质细胞极化可改善实验性自身免疫性脑脊髓炎（EAE）的严重程度
DOI：
10.1016/j.jaut.2019.04.020
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发表时间：
2019-08-01
影响因子：
12.8
通讯作者：
Wang, Honghao
中科院分区：
文献类型：
--
作者：
Liu, Baozhu;Gu, Yong;Wang, Honghao
Toll样受体4（TLR 4）在激活先天免疫系统识别病原体过程中起关键作用。在多发性硬化（MS）的发病机制中，活化的TLR 4与髓样分化初级应答基因88（MyD 88）一起产生促进小胶质细胞分化成M1表型的炎性微环境，白细胞介素-1受体相关激酶（IRAK）-M在中枢神经系统（CNS）的小胶质细胞中特异性表达并作为TLR 4-MyD 88信号通路的负调节剂。此外，先前的研究表明IRAK-M促进2型小胶质细胞的分化;然而，其在MS中的作用尚未被探索。在本研究中，我们证明了IRAK-M表达在EAE期间升高，IRAK-M-/-小鼠显著加速了病程并增加了疾病的严重程度，伴随着M1小胶质细胞浸润的明显增加。总之，这些数据表明IRAK-M通过下调TLR 4-MyD 88信号通路显著改善EAE发作，这最终导致小胶质细胞中M2表型的分化。我们的研究表明，IRAK-M可能是治疗MS的潜在治疗靶点。
Toll-like receptor 4 (TLR4) play a key role in activating the innate immune system during pathogen recognition. In the pathogenesis of multiple sclerosis (MS), activated TLR4 together with myeloid differentiation primary response gene 88 (MyD88) produce an inflammatory microenvironment that promotes the differentiation of microglia into the M1 phenotype, who plays a key role in the pathogenesis of MS. Interleukin-1 receptor-associated kinase (IRAK)-M is specifically expressed in microglia in central nervous system (CNS) and act as a negative regulator of TLR4-MyD88 signaling pathway. Moreover, previous studies have shown that IRAK-M promotes the differentiation of type 2 microglia; however, its role in MS has not been explored. In the present study, we demonstrated that IRAK-M expression is elevated during EAE, and IRAK-M-/- mice significantly accelerated course and increased severity of disease, accompanied by a visible increase of the M1 microglia infiltrated. In conclusion, these data indicates that IRAK-M significantly improves EAE onset through down-regulation of the TLR4-MyD88 signaling pathway, which finally leads to differentiation of M2 phenotype in the microglia. Our study suggests that IRAK-M may be a potential therapeutic target for the treatment of MS.