Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

Jing Liu; Danmin Shen; Chao Wei; Weihua Wu; Zhaoli Luo; Liye Hu; Zhongnan Xiao; Tingting Hu; Qingyu Sun; Xiaotong Wang; Yumeng Ding; Meng Liu; Miaoyi Pang; Kaiyuan Gai; Yiran Ma; Yichen Tian; Yan Yu; Peipei Wang; Yun Guan; Meng Xu; Fei Yang; Qian Li

doi:10.1016/j.isci.2022.105527

Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

iScience. 2022 Nov 13;25(12):105527. doi: 10.1016/j.isci.2022.105527. eCollection 2022 Dec 22.

Authors

Jing Liu¹, Danmin Shen², Chao Wei¹, Weihua Wu², Zhaoli Luo², Liye Hu², Zhongnan Xiao², Tingting Hu¹, Qingyu Sun¹, Xiaotong Wang¹, Yumeng Ding¹, Meng Liu¹, Miaoyi Pang³, Kaiyuan Gai³, Yiran Ma³, Yichen Tian³, Yan Yu⁴, Peipei Wang¹, Yun Guan⁵, Meng Xu⁶, Fei Yang^{1

7}, Qian Li^{2

7

8}

Affiliations

¹ Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
³ School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
⁴ Chinese Institute of Rehabilitation Science, China Rehabilitation Research Center, Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing 100068, China.
⁵ Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Musculoskeletal Tumor, Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100142, China.
⁷ Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China.
⁸ Key Laboratory of Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China.

Abstract

Promoting microglial/macrophage (M/Mφ) phagocytosis accelerates hematoma clearance and improves the prognosis of intracerebral hemorrhagic stroke (ICH). Cation channels such as Piezo1 modulate bacterial clearance by regulating M/Mφ. Whether LRRC8A, an anion channel, affects M/Mφ erythrophagocytosis and functional recovery after ICH was investigated here. We found that LRRC8A is highly expressed on M/Mφ in the perihematomal region of ICH mice. Conditional knockout of Lrrc8a in M/Mφ or treatment with an LRRC8A channel blocker accelerated hematoma clearance, reduced neuronal death, and improved functional recovery after ICH. Mechanistically, the LRRC8A channel inhibition promoted M/Mφ phagocytosis by activating AMP-activated protein kinase (AMPK), thereby inducing nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and increasing Cd36 transcription. Our findings illuminate the regulation of M/Mφ phagocytosis by the LRRC8A channel via the AMPK-Nrf2-CD36 pathway after ICH, suggesting that LRRC8A is a potential target for hematoma clearance in ICH treatment.

Keywords: Immunology and neurology.