LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1-mediated signalling pathways
LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1-mediated signalling pathways
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LRRK2 通过调节趋化因子 (C-X3-C) 受体 1 介导的信号通路来调节小胶质细胞活性
DOI：
10.1093/hmg/ddw194
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发表时间：
2016-08-15
影响因子：
3.5
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
--
作者：
Ma, Bo;Xu, Leyan;Cai, Huaibin
富含亮氨酸重复序列激酶2（LRRK 2）的多个错义突变与帕金森病（PD）有关，帕金森病是最常见的退行性运动障碍。LRRK 2由神经元和小胶质细胞表达，小胶质细胞是大脑中的住宅免疫细胞。越来越多的证据支持LRRK 2在调节小胶质细胞活性中的作用，其中Lrrk 2缺失的啮齿动物小胶质细胞对内毒素脂多糖（LPS）显示较少的炎症反应。然而，潜在的分子机制仍然难以捉摸。趋化因子（C-X3-C）受体1（CX 3CR 1）主要由小胶质细胞表达，抑制小胶质细胞炎症，同时促进迁移。使用全基因组微阵列筛选，我们发现Cx 3cr 1 mRNA水平在Lrrk 2敲除（Lrrk 2（-/-））小鼠的小胶质细胞中显著较高。CX 3CR 1蛋白的总水平和细胞表面水平也显著增加。与增强的CX 3CR 1表达相关，Lrrk 2-null小胶质细胞向CX 3CR 1的内源性配体fractalkine（CX 3CL 1）的来源迁移更快，行进更长的距离。为了研究体内CX 3CR 1升高的影响，我们比较了Lrrk 2（-/-）敲除小鼠与Cx 3cr 1杂合和纯合敲除背景的纹状体中LPS诱导的炎症。我们发现，Cx 3cr 1的完全缺失恢复了Lrrk 2（-/-）小胶质细胞对LPS刺激的反应性。总之，我们的研究结果揭示了以前未知的调节作用LRRK 2在CX 3CR 1信号传导，并表明CX 3CR 1活性的增加有助于减弱炎症反应Lrrk 2空小胶质细胞。
Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the most common degenerative movement disorder. LRRK2 is expressed by both neurons and microglia, the residential immune cells in the brain. Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory response to endotoxin lipopolysaccharide (LPS). The underlying molecular mechanism, however, remains elusive. Chemokine (C-X3-C) receptor 1 (CX3CR1), predominantly expressed by microglia, suppresses microglial inflammation while promotes migration. Using whole-genome microarray screening, we found that Cx3cr1 mRNA levels were substantially higher in microglia derived from Lrrk2 knockout (Lrrk2(-/-)) mice. The total and cell surface levels of CX3CR1 proteins were also remarkably increased. In correlation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longer distance toward the source of fractalkine (CX3CL1), an endogenous ligand of CX3CR1. To investigate the impact of CX3CR1 elevation in vivo, we compared LPS-induced inflammation in the striatum of Lrrk2(-/-) knockout mice with Cx3cr1 heterozygous and homozygous knockout background. We found that a complete loss of Cx3cr1 restored the responsiveness of Lrrk2(-/-) microglia to LPS stimulation. In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia.