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
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.
