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

• DOI: 10.1016/j.isci.2022.105527
• Publication Date: 2022-11-13T23:10:35Z
• Authors: 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
• Keywords: CD36; Conditional gene knockout

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.