Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice

Tian Zhou, Yuxin Li, Xiaoyu Li, Fanzhuo Zeng, Yanxia Rao, Yang He, Yafei Wang, Meizhen Liu, Dali Li, Zhen Xu, Xin Zhou, Siling Du, Fugui Niu, Jiyun Peng, Xifan Mei, Sheng-Jian Ji, Yousheng Shu, Wei Lu, Feifan Guo, Tianzhun Wu, Ti-Fei Yuan, Ying Mao and Bo Peng ()
Additional contact information
Tian Zhou: Chinese Academy of Sciences
Yuxin Li: Fudan University
Xiaoyu Li: Fudan University
Fanzhuo Zeng: Fudan University
Yanxia Rao: Fudan University
Yang He: Fudan University
Yafei Wang: Fudan University
Meizhen Liu: East China Normal University
Dali Li: East China Normal University
Zhen Xu: Chinese Academy of Sciences
Xin Zhou: Fudan University
Siling Du: Fudan University
Fugui Niu: Southern University of Science and Technology
Jiyun Peng: Nanchang University
Xifan Mei: The Third Affiliated Hospital of Jinzhou Medical University
Sheng-Jian Ji: Southern University of Science and Technology
Yousheng Shu: Fudan University
Wei Lu: Fudan University
Feifan Guo: Fudan University
Tianzhun Wu: Chinese Academy of Sciences
Ti-Fei Yuan: Shanghai Jiao Tong University School of Medicine
Ying Mao: Fudan University
Bo Peng: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33932-3

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