2. Academic Validation
  3. Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

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

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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