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.

 抽象的

小胶质细胞激活诱导的神经炎症与帕金森病（PD）的发生密切相关。巨自噬/自噬调节许多生物过程，但自噬在 PD 发育过程中小胶质细胞激活中的作用仍不清楚。在这项研究中，我们发现小胶质细胞Atg5的缺失会导致小鼠出现 PD 样症状，其特征是运动协调和认知学习受损、酪氨酸羟化酶 (TH) 神经元丧失、神经炎症加剧以及纹状体中多巴胺水平降低。从机制上讲，我们发现自噬的抑制导致小胶质细胞中通过PDE10A（磷酸二酯酶 10A）-环磷酸腺苷（cAMP）信号通路激活 NLRP3（包含 3 个 NLR 家族的热蛋白结构域）炎症小体，并依次上调下游 IL1B/IL-1β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。通过使用 NLRP3 特异性抑制剂 MCC950 抑制 NLRP3 炎症小体激活，降低 MIF 表达和神经炎症水平，并挽救黑质 (SN) 中 TH 神经元的损失。有趣的是，我们发现PD患者血清MIF水平显着升高。综上所述，我们的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：条件性敲除； NOS2/INOS：一氧化氮合酶 2，诱导型； IL1B：白细胞介素1β； ITGAM/CD-11b：整合素αM/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：包含3个NLR家族pyrin结构域； PBS：磷酸盐缓冲盐水； PD：帕金森病； PDE10A：磷酸二酯酶10A； SN：大量黑质； TH：酪氨酸羟化酶； TNF：肿瘤坏死因子； WT：野生型。