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

iScience (Dec 2022)

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

Affiliations

Jing Liu: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Danmin Shen: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Chao Wei: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Weihua Wu: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Zhaoli Luo: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Liye Hu: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Zhongnan Xiao: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Tingting Hu: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Qingyu Sun: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Xiaotong Wang: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yumeng Ding: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Meng Liu: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Miaoyi Pang: School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Kaiyuan Gai: School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yiran Ma: School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yichen Tian: School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yan Yu: Chinese Institute of Rehabilitation Science, China Rehabilitation Research Center, Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing 100068, China
Peipei Wang: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yun Guan: Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
Meng Xu: Department of Musculoskeletal Tumor, Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100142, China; Corresponding author
Fei Yang: Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China; Corresponding author
Qian Li: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China; Key Laboratory of Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China; Corresponding author

Journal volume & issue: Vol. 25, no. 12
p. 105527

Abstract

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Summary: 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.

Immunology and neurology

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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