LRP1 expression in microglia is protective during CNS autoimmunity.
LRP1 expression in microglia is protective during CNS autoimmunity.
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DOI：
10.1186/s40478-016-0343-2
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发表时间：
2016-07-11
影响因子：
7.1
通讯作者：
Gaultier A
中科院分区：
文献类型：
--
作者：
Chuang TY;Guo Y;Seki SM;Rosen AM;Johanson DM;Mandell JW;Lucchinetti CF;Gaultier A
多发性硬化症是一种毁灭性的神经系统疾病，其特征是中枢神经系统髓鞘的自身免疫破坏。虽然已知T细胞是导致MS病理的免疫反应的协调者，但CNS驻留和外周浸润性髓系细胞的确切作用还不太清楚。在这里，我们探讨了在多发性硬化症的背景下，低密度脂蛋白受体相关蛋白-1(LRP1)的髓系细胞功能，LRP1是一种参与髓鞘清除和炎症反应的清道夫受体。支持其在多发性硬化症病理中的中心作用，我们发现与周围健康组织相比，LRP1在多发性硬化症皮损中的表达增加。使用两个遗传小鼠模型，我们发现LRP1在小胶质细胞中的缺失，而不是在外周巨噬细胞中的缺失，对多发性硬化症的动物模型实验性自身免疫性脑脊髓炎的进展产生负面影响。我们进一步证明，实验性自身免疫性脑脊髓炎疾病严重程度的增加并不是由于CX3CR1基因座的单倍体缺陷造成的。在细胞水平上，缺乏LRP1的小胶质细胞具有致炎表型，其特征是变形虫形态和炎性介质肿瘤坏死因子-α的产生增加。我们还表明，LRP1通过MyD88依赖的途径在髓系细胞中作为核因子-kB激活的强大抑制因子，潜在地解释了在小胶质细胞缺乏LRP1表达的小鼠中观察到的疾病严重性的增加。综上所述，我们的数据表明，LRP1在小胶质细胞中的功能是在炎症性损伤时保持这些细胞处于抗炎和神经保护状态，包括实验性自身免疫性脑脊髓炎和可能的多发性硬化症。本文的在线版本(doi：10.1186/s40478-0160343-2)包含补充材料，授权用户可以使用。
Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis. The online version of this article (doi:10.1186/s40478-016-0343-2) contains supplementary material, which is available to authorized users.