The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function
The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orche...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823003729 |
| _version_ | 1797422665913335808 |
|---|---|
| author | Xiaoyan Wu Xin Yi Boxin Zhao Yuanxing Zhi Ziwei Xu Ying Cao Xiong Cao Jianxin Pang Ken Kin Lam Yung Shiqing Zhang Shuwen Liu Pingzheng Zhou |
| author_facet | Xiaoyan Wu Xin Yi Boxin Zhao Yuanxing Zhi Ziwei Xu Ying Cao Xiong Cao Jianxin Pang Ken Kin Lam Yung Shiqing Zhang Shuwen Liu Pingzheng Zhou |
| author_sort | Xiaoyan Wu |
| collection | DOAJ |
| description | The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+ efflux for NLRP3 stimuli that require K+ efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice with Lrrc8a deficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases. |
| first_indexed | 2024-03-09T07:36:40Z |
| format | Article |
| id | doaj.art-d8d493bd9e1d4acd8d32e06aaa0de23a |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T07:36:40Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-d8d493bd9e1d4acd8d32e06aaa0de23a2023-12-03T05:39:43ZengElsevierPharmacological Research1096-11862023-12-01198107016The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria functionXiaoyan Wu0Xin Yi1Boxin Zhao2Yuanxing Zhi3Ziwei Xu4Ying Cao5Xiong Cao6Jianxin Pang7Ken Kin Lam Yung8Shiqing Zhang9Shuwen Liu10Pingzheng Zhou11Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaKey Laboratory of Mental Health of the Ministry of Education, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Science and Environmental Studies, the Education University of Hong Kong, Hong Kong, ChinaJNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou, China; Corresponding authors.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; Corresponding authors.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; Corresponding authors.The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+ efflux for NLRP3 stimuli that require K+ efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice with Lrrc8a deficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases.http://www.sciencedirect.com/science/article/pii/S1043661823003729LRRC8Cell volume regulationInnate immunitySepsisMacrophage activationImmunometabolism |
| spellingShingle | Xiaoyan Wu Xin Yi Boxin Zhao Yuanxing Zhi Ziwei Xu Ying Cao Xiong Cao Jianxin Pang Ken Kin Lam Yung Shiqing Zhang Shuwen Liu Pingzheng Zhou The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function Pharmacological Research LRRC8 Cell volume regulation Innate immunity Sepsis Macrophage activation Immunometabolism |
| title | The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function |
| title_full | The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function |
| title_fullStr | The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function |
| title_full_unstemmed | The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function |
| title_short | The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function |
| title_sort | volume regulated anion channel vrac regulates nlrp3 inflammasome by modulating itaconate efflux and mitochondria function |
| topic | LRRC8 Cell volume regulation Innate immunity Sepsis Macrophage activation Immunometabolism |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823003729 |
| work_keys_str_mv | AT xiaoyanwu thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT xinyi thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT boxinzhao thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT yuanxingzhi thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT ziweixu thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT yingcao thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT xiongcao thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT jianxinpang thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT kenkinlamyung thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT shiqingzhang thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT shuwenliu thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT pingzhengzhou thevolumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT xiaoyanwu volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT xinyi volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT boxinzhao volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT yuanxingzhi volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT ziweixu volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT yingcao volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT xiongcao volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT jianxinpang volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT kenkinlamyung volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT shiqingzhang volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT shuwenliu volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction AT pingzhengzhou volumeregulatedanionchannelvracregulatesnlrp3inflammasomebymodulatingitaconateeffluxandmitochondriafunction |