Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice
Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice
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小胶质细胞自噬缺陷通过加速小鼠炎症小体激活导致帕金森病样症状
DOI：
10.1080/15548627.2020.1719723
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发表时间：
2020-02-02
期刊：
影响因子：
13.3
通讯作者：
Yuan, Zengqiang
中科院分区：
文献类型：
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作者：
Cheng, Jinbo;Liao, Yajin;Yuan, Zengqiang
小胶质细胞激活诱导的神经炎症与帕金森病（PD）的发展密切相关。巨噬/自噬调节许多生物过程，但自噬在PD发展过程中对小胶质细胞激活的作用仍不清楚。在这项研究中，我们发现小胶质细胞Atg5的缺失引起小鼠pd样症状，其特征是运动协调和认知学习障碍，酪氨酸羟化酶（TH）神经元的丧失，神经炎症的增强和纹状体多巴胺水平的降低。在机制上，我们发现自噬抑制通过PDE10A（磷酸二酯酶10A） -环磷酸腺苷（cAMP）信号传导导致小胶质细胞NLRP3 （NLR家族pyrin结构域3）炎性体激活，而下游IL1B/IL-1β的顺序上调反过来增加了促炎细胞因子MIF（巨噬细胞迁移抑制因子[糖基化抑制因子]）的表达。通过给予NLRP3特异性抑制剂MCC950抑制NLRP3炎性体激活，降低MIF表达和神经炎症水平，挽救实质黑质（SN）中TH神经元的损失。有趣的是，我们发现PD患者的血清MIF水平显著升高。综上所述，我们的研究结果揭示了自噬在小胶质细胞激活驱动的PD样症状中的重要作用，从而为PD的临床治疗提供了潜在的靶点。缩写：ATG：自噬相关；cAMP：环磷酸腺苷；cKO：条件击倒；NOS2/INOS：一氧化氮合酶2，诱导型；IL1B：白细胞介素1 β；ITGAM/CD-11b：整合素M/分化分子簇11B；MAP1LC3：微管相关蛋白1轻链3；MIF：巨噬细胞迁移抑制因子（糖基化抑制因子）；NLRP3: NLR家族pyrin结构域含3；PBS：磷酸盐缓冲盐水；PD：帕金森病；PDE10A：磷酸二酯酶10A；SN：大量黑；TH：酪氨酸羟化酶；TNF：肿瘤坏死因子；WT：野生型。
ABSTRACT Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.