IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis
Abstract The activation of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers pyroptosis proinflammatory cell death in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanisms of the inflammatory processes of microglia in EAE remai...
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Nature Publishing Group
2023-02-01
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Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-023-05621-6 |
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author | Yuanyuan Wang Shanshan Pei Zhuhe Liu Yuewen Ding Tinglin Qian Haixia Wen Ssu-Wei Hsu Zheyi Zhou Jun Zhang Honghao Wang |
author_facet | Yuanyuan Wang Shanshan Pei Zhuhe Liu Yuewen Ding Tinglin Qian Haixia Wen Ssu-Wei Hsu Zheyi Zhou Jun Zhang Honghao Wang |
author_sort | Yuanyuan Wang |
collection | DOAJ |
description | Abstract The activation of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers pyroptosis proinflammatory cell death in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanisms of the inflammatory processes of microglia in EAE remain unclear. Our previous studies suggested that interleukin-1 receptor-associated kinase (IRAK)-M down-regulates the toll-like receptor 4/interleukin-1 receptor signaling pathway. Here, we used IRAK-M knockout (IRAK-M−/−) mice and their microglia to dissect the role of IRAK-M in EAE. We found that deletion of IRAK-M increased the incidence rate and exacerbated the clinical symptoms in EAE mice. We then found that IRAK-M deficiency promoted the activation of microglia, activated NLRP3 inflammasomes, and enhanced GSDMD-mediated pyroptosis in the microglia of EAE. In contrast, over-expression of IRAK-M exerted inhibitory effects on neuroinflammation, NLRP3 activation, and pyroptosis. Moreover, IRAK-M deficiency enhanced the phosphorylation of IRAK1, while IRAK-M over-expression downregulated the level of phosphorylated IRAK1. Finally, we found upregulated binding of IRAK1 and TNF receptor-associated factor 6 (TRAF6) in IRAK-M−/− EAE mice compared to WT mice, which was blocked in AAVIRAK-M EAE mice. Our study reveals a complex signaling network of IRAK-M, which negatively regulates microglial NLRP3 inflammasomes and pyroptosis by inhibiting IRAK1 phosphorylation during EAE. These findings suggest a potential target for the novel therapeutic approaches of multiple sclerosis (MS)/EAE and NLRP3-related inflammatory diseases. |
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issn | 2041-4889 |
language | English |
last_indexed | 2024-04-10T15:40:55Z |
publishDate | 2023-02-01 |
publisher | Nature Publishing Group |
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series | Cell Death and Disease |
spelling | doaj.art-5f4c57c709304b4bae20b21773b174e42023-02-12T12:24:04ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211210.1038/s41419-023-05621-6IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitisYuanyuan Wang0Shanshan Pei1Zhuhe Liu2Yuewen Ding3Tinglin Qian4Haixia Wen5Ssu-Wei Hsu6Zheyi Zhou7Jun Zhang8Honghao Wang9Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Nanfang Hospital, Southern Medical UniversityDepartment of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyDepartment of Internal Medicine, University of California at DavisDepartment of Neurology, Hospital of Liuzhou Traditional Chinese MedicineDepartment of Internal Medicine, University of California at DavisDepartment of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyAbstract The activation of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers pyroptosis proinflammatory cell death in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanisms of the inflammatory processes of microglia in EAE remain unclear. Our previous studies suggested that interleukin-1 receptor-associated kinase (IRAK)-M down-regulates the toll-like receptor 4/interleukin-1 receptor signaling pathway. Here, we used IRAK-M knockout (IRAK-M−/−) mice and their microglia to dissect the role of IRAK-M in EAE. We found that deletion of IRAK-M increased the incidence rate and exacerbated the clinical symptoms in EAE mice. We then found that IRAK-M deficiency promoted the activation of microglia, activated NLRP3 inflammasomes, and enhanced GSDMD-mediated pyroptosis in the microglia of EAE. In contrast, over-expression of IRAK-M exerted inhibitory effects on neuroinflammation, NLRP3 activation, and pyroptosis. Moreover, IRAK-M deficiency enhanced the phosphorylation of IRAK1, while IRAK-M over-expression downregulated the level of phosphorylated IRAK1. Finally, we found upregulated binding of IRAK1 and TNF receptor-associated factor 6 (TRAF6) in IRAK-M−/− EAE mice compared to WT mice, which was blocked in AAVIRAK-M EAE mice. Our study reveals a complex signaling network of IRAK-M, which negatively regulates microglial NLRP3 inflammasomes and pyroptosis by inhibiting IRAK1 phosphorylation during EAE. These findings suggest a potential target for the novel therapeutic approaches of multiple sclerosis (MS)/EAE and NLRP3-related inflammatory diseases.https://doi.org/10.1038/s41419-023-05621-6 |
spellingShingle | Yuanyuan Wang Shanshan Pei Zhuhe Liu Yuewen Ding Tinglin Qian Haixia Wen Ssu-Wei Hsu Zheyi Zhou Jun Zhang Honghao Wang IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis Cell Death and Disease |
title | IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis |
title_full | IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis |
title_fullStr | IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis |
title_full_unstemmed | IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis |
title_short | IRAK-M suppresses the activation of microglial NLRP3 inflammasome and GSDMD-mediated pyroptosis through inhibiting IRAK1 phosphorylation during experimental autoimmune encephalomyelitis |
title_sort | irak m suppresses the activation of microglial nlrp3 inflammasome and gsdmd mediated pyroptosis through inhibiting irak1 phosphorylation during experimental autoimmune encephalomyelitis |
url | https://doi.org/10.1038/s41419-023-05621-6 |
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