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.
Jing Liu  1 ,  Danmin Shen  2 ,  Chao Wei  1 ,  Weihua Wu  2 ,  Zhaoli Luo  2 ,  Liye Hu  2 ,  Zhongnan Xiao  2 ,  Tingting Hu  1 ,  Qingyu Sun  1 ,  Xiaotong Wang  1 ,  Yumeng Ding  1 ,  Meng Liu  1 ,  Miaoyi Pang  3 ,  Kaiyuan Gai  3 ,  Yiran Ma  3 ,  Yichen Tian  3 ,  Yan Yu  4 ,  Peipei Wang  1 ,  Yun Guan  5 ,  Meng Xu  6 ,  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.
PMID: 36465125 DOI: 10.1016/j.isci.2022.105527
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.
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