Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke
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 erythrophag...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-12-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222017990 |
| _version_ | 1811304238575255552 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Jing Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T08:02:22Z |
| format | Article |
| id | doaj.art-544c5bf95b114822b115df1745ee21cc |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-13T08:02:22Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-544c5bf95b114822b115df1745ee21cc2022-12-22T02:55:15ZengElsevieriScience2589-00422022-12-012512105527Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic strokeJing Liu0Danmin Shen1Chao Wei2Weihua Wu3Zhaoli Luo4Liye Hu5Zhongnan Xiao6Tingting Hu7Qingyu Sun8Xiaotong Wang9Yumeng Ding10Meng Liu11Miaoyi Pang12Kaiyuan Gai13Yiran Ma14Yichen Tian15Yan Yu16Peipei Wang17Yun Guan18Meng Xu19Fei Yang20Qian Li21Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaSchool of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaSchool of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaSchool of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaSchool of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaChinese Institute of Rehabilitation Science, China Rehabilitation Research Center, Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing 100068, ChinaDepartment of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, ChinaDepartment of Anesthesiology and Critical Care Medicine, the Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USADepartment of Musculoskeletal Tumor, Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100142, China; Corresponding authorDepartment 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 authorDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222017990Immunology and neurology |
| spellingShingle | 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 Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke iScience Immunology and neurology |
| title | Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| title_full | Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| title_fullStr | Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| title_full_unstemmed | Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| title_short | Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| title_sort | inhibition of the lrrc8a channel promotes microglia macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke |
| topic | Immunology and neurology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222017990 |
| work_keys_str_mv | AT jingliu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT danminshen inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT chaowei inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT weihuawu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT zhaoliluo inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT liyehu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT zhongnanxiao inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT tingtinghu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT qingyusun inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT xiaotongwang inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT yumengding inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT mengliu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT miaoyipang inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT kaiyuangai inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT yiranma inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT yichentian inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT yanyu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT peipeiwang inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT yunguan inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT mengxu inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT feiyang inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke AT qianli inhibitionofthelrrc8achannelpromotesmicrogliamacrophagephagocytosisandimprovesoutcomesafterintracerebralhemorrhagicstroke |