Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China.
Nat Commun. 2022 Oct 24;13(1):6233. doi: 10.1038/s41467-022-33932-3.
Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.
小胶质细胞是中枢神经系统 (CNS) 中的重要免疫细胞，它们在整个生命周期中都会发生更替。如果不能及时清除小胶质细胞碎片，积累的碎片可能会影响 CNS 的功能。清除小胶质细胞碎片对于 CNS 的内稳态至关重要。然而，其潜在的机制仍不清楚。我们在这里研究了死亡的小胶质细胞是如何被清除的。我们发现，尽管小胶质细胞在体外可以吞噬小胶质细胞碎片，但区域依赖性竞争阻碍了体内小胶质细胞吞噬小胶质细胞碎片。相比之下，小胶质细胞碎片主要被大脑中的星形胶质细胞吞噬，这一过程由 C4b 调理素作用促进。被吞噬的小胶质细胞片段随后在星形胶质细胞中通过 RUBICON 依赖性 LC3 相关吞噬作用 (LAP) 降解，这是一种非典型自噬形式。干扰 C4b 介导的吞噬作用和随后的 LAP 分别破坏了小胶质细胞碎片的清除和降解。综上所述，我们阐明了小胶质细胞碎片在小鼠体内清除的细胞和分子机制，扩展了对 CNS 内稳态维持的认识。
