LRRK2 inhibition attenuates microglial inflammatory responses.
LRRK2 inhibition attenuates microglial inflammatory responses.
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DOI：
10.1523/jneurosci.5601-11.2012
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
West AB
中科院分区：
文献类型：
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作者：
Moehle MS;Webber PJ;Tse T;Sukar N;Standaert DG;DeSilva TM;Cowell RM;West AB
富亮氨酸重复序列激酶2（LRRK2）的错义突变导致晚发性帕金森病，LRRK2的常见遗传变异改变了对克罗恩病和麻风病的易感性。外周血单核细胞和巨噬细胞中LRRK2的高水平表达表明LRRK2在这些细胞中的作用，但对LRRK2在脑免疫细胞中的表达和功能知之甚少。在这里，我们证明了LRRK 2在介导小胶质细胞促炎症反应和形态中的作用。在神经炎症的鼠模型中，我们观察到小胶质细胞中LRRK2的稳健诱导。用TLR4刺激的大鼠原代小胶质细胞的实验表明，炎症增加LRRK2活性和表达，而抑制LRRK2激酶活性或敲低蛋白质减弱TNFα分泌和iNOS诱导。LRRK2抑制阻断TLR4刺激的小胶质细胞突起生长并损害ADP刺激的小胶质细胞趋化性。然而，肌动蛋白抑制剂，表型抑制过程的生长和趋化不能改变TLR4刺激TNFα分泌和诱导型一氧化氮合酶的诱导，这表明LRRK2作为一种应激反应激酶的细胞骨架控制的上游。这些数据表明LRRK2在调节大脑免疫细胞的反应中，并进一步暗示小胶质细胞参与迟发性PD。
Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson disease, and common genetic variation in LRRK2 modifies susceptibility to Crohn disease and leprosy. High levels of LRRK2 expression in peripheral monocytes and macrophages suggest a role for LRRK2 in these cells, yet little is known about LRRK2 expression and function in immune cells of the brain. Here, we demonstrate a role for LRRK2 in mediating microglial pro-inflammatory responses and morphology. In a murine model of neuroinflammation, we observe robust induction of LRRK2 in microglia. Experiments with TLR4-stimulated rat primary microglia show that inflammation increases LRRK2 activity and expression while inhibition of LRRK2 kinase activity or knockdown of protein attenuates TNFα secretion and iNOS induction. LRRK2 inhibition blocks TLR4 stimulated microglial process outgrowth and impairs ADP stimulated microglial chemotaxis. However, actin inhibitors that phenocopy inhibition of process outgrowth and chemotaxis fail to modify TLR4 stimulation of TNFα secretion and iNOS induction, suggesting LRRK2 acts upstream of cytoskeleton control as a stress-responsive kinase. These data demonstrate LRRK2 in regulating responses in immune cells of the brain and further implicate microglial involvement in late-onset PD.