IFP35 family proteins promote neuroinflammation and sclerosis
IFP35 family proteins promote neuroinflammation and sclerosis
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IFP35 家族蛋白促进神经炎症和多发性硬化症
DOI：
10.1073/pnas.2102642118
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发表时间：
2021-08-10
影响因子：
11.1
通讯作者：
Liang, Huanhuan
中科院分区：
文献类型：
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作者：
Jing, Xizhong;Yao, Yongjie;Liang, Huanhuan
T细胞和小胶质细胞的过度活化代表了人类多发性硬化症（MS）发病机制的标志。然而，过度激活这些免疫细胞的调节分子仍有待鉴定。以前，我们报道了细胞外IFP 35家族蛋白，包括IFP 35和NMI，在外周活化巨噬细胞作为促炎分子。在这里，我们研究了它们在中枢神经系统（CNS）和外周神经炎症过程中的作用。我们对临床转录组数据的分析表明，MS患者IFP 35家族蛋白的表达上调。另外的体外研究表明，IFP 35和NMI由多个细胞释放。IFP 35和NMI随后通过TLR 4途径触发小胶质细胞的核因子κ B依赖性活化。重要的是，我们发现IFP 35和NMI都激活了树突状细胞，并促进幼稚T细胞分化为Th 1和Th 17细胞。Nmi（-/-）、Ifp 35（-/-）或抗IFP 35中和抗体可减轻免疫细胞在中枢神经系统的浸润和脱髓鞘，从而减轻实验性自身免疫性脑脊髓炎的严重程度。总之，我们的研究结果揭示了IFP 35家族蛋白促进T细胞和小胶质细胞过度活化的一种迄今未知的机制，并提出了研究MS发病机制的途径。
Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B- dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naive T cell differentiation into Th1 and Th17 cells. Nmi(-/-), Ifp35(-/-), or administration of neutralizing antibodies against IFP35 alleviated the immune cells' infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.