α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis
BackgroundNicotine exerts direct effects on multiple cell types in the cardiovascular system by associating with its high-affinity nicotinic acetylcholine receptors (nAchRs). Lipid raft is a membrane microdomain that recruits various receptors and signaling molecules for coordinating cellular immune...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.724699/full |
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| author | Fengqi Duan Cheng Zeng Sijun Liu Jianfeng Gong Jia Hu Hongyu Li Hongmei Tan Hongmei Tan Hongmei Tan |
| author_facet | Fengqi Duan Cheng Zeng Sijun Liu Jianfeng Gong Jia Hu Hongyu Li Hongmei Tan Hongmei Tan Hongmei Tan |
| author_sort | Fengqi Duan |
| collection | DOAJ |
| description | BackgroundNicotine exerts direct effects on multiple cell types in the cardiovascular system by associating with its high-affinity nicotinic acetylcholine receptors (nAchRs). Lipid raft is a membrane microdomain that recruits various receptors and signaling molecules for coordinating cellular immune response and many others signaling processes. Here, we aim to identify the essential role of lipid raft in mediating nicotine-triggered inflammatory and nicotine-accelerated atherosclerosis, and to figure out the specific receptor of nicotine-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation in macrophage.Methods and ResultsApoE–/– mice were fed with a high-fat diet to build atherosclerosis model. Methyl-β-cyclodextrin was used to interrupt intact lipid raft. We confirmed that nicotine triggered NLRP3 inflammasome activation and induced macrophage migration into atherosclerotic plaque, thus accelerated atherosclerosis in apoE–/– mice fed with a high-fat diet. Mechanically, nicotine increased the expression of α1-nAChR and stimulated the accumulation of α1-nAChR in lipid raft, leading to NLRP3 inflammasome activation in macrophage. Conversely, silencing of α1-nAChR in macrophage sufficiently blocked the pro-inflammasome activation effect of nicotine, indicating that α1-nAChR was the specific receptor for nicotine in triggering NLRP3 inflammasome in macrophage. Furthermore, both the destruction of lipid raft by methyl-β-cyclodextrin and the interference of lipid raft clustering by silencing acid sphingomyelinase reversed nicotine-induced NLRP3 inflammasome activation by reducing the accumulation of α1-nAChR in lipid raft in macrophage, suggesting lipid raft–mediated accumulation of α1-nAChR was the key event in regulating the pro-inflammatory effects of nicotine in macrophage. Importantly, nicotine-induced NLRP3 inflammasome activation and macrophage migration into atherosclerotic plaque were reversed by methyl-β-cyclodextrin, making a significant improvement for atherosclerosis in apoE–/– mice fed with a high-fat diet.Conclusionα1-nAChR-mediated signaling through lipid raft is required for NLRP3 inflammasome activation and pro-atherosclerotic property of nicotine. |
| first_indexed | 2024-12-21T20:55:54Z |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-21T20:55:54Z |
| publishDate | 2021-08-01 |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-4b402f3ff0654d1fb76c4e5b925c13cc2022-12-21T18:50:34ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.724699724699α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated AtherosclerosisFengqi Duan0Cheng Zeng1Sijun Liu2Jianfeng Gong3Jia Hu4Hongyu Li5Hongmei Tan6Hongmei Tan7Hongmei Tan8Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaLaboratory Animal Center, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaLaboratory Animal Center, Sun Yat-sen University, Guangzhou, ChinaThe Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaBackgroundNicotine exerts direct effects on multiple cell types in the cardiovascular system by associating with its high-affinity nicotinic acetylcholine receptors (nAchRs). Lipid raft is a membrane microdomain that recruits various receptors and signaling molecules for coordinating cellular immune response and many others signaling processes. Here, we aim to identify the essential role of lipid raft in mediating nicotine-triggered inflammatory and nicotine-accelerated atherosclerosis, and to figure out the specific receptor of nicotine-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation in macrophage.Methods and ResultsApoE–/– mice were fed with a high-fat diet to build atherosclerosis model. Methyl-β-cyclodextrin was used to interrupt intact lipid raft. We confirmed that nicotine triggered NLRP3 inflammasome activation and induced macrophage migration into atherosclerotic plaque, thus accelerated atherosclerosis in apoE–/– mice fed with a high-fat diet. Mechanically, nicotine increased the expression of α1-nAChR and stimulated the accumulation of α1-nAChR in lipid raft, leading to NLRP3 inflammasome activation in macrophage. Conversely, silencing of α1-nAChR in macrophage sufficiently blocked the pro-inflammasome activation effect of nicotine, indicating that α1-nAChR was the specific receptor for nicotine in triggering NLRP3 inflammasome in macrophage. Furthermore, both the destruction of lipid raft by methyl-β-cyclodextrin and the interference of lipid raft clustering by silencing acid sphingomyelinase reversed nicotine-induced NLRP3 inflammasome activation by reducing the accumulation of α1-nAChR in lipid raft in macrophage, suggesting lipid raft–mediated accumulation of α1-nAChR was the key event in regulating the pro-inflammatory effects of nicotine in macrophage. Importantly, nicotine-induced NLRP3 inflammasome activation and macrophage migration into atherosclerotic plaque were reversed by methyl-β-cyclodextrin, making a significant improvement for atherosclerosis in apoE–/– mice fed with a high-fat diet.Conclusionα1-nAChR-mediated signaling through lipid raft is required for NLRP3 inflammasome activation and pro-atherosclerotic property of nicotine.https://www.frontiersin.org/articles/10.3389/fcell.2021.724699/fulllipid raftnicotineatherosclerosisα1-nAChRsNLRP3inflammasome |
| spellingShingle | Fengqi Duan Cheng Zeng Sijun Liu Jianfeng Gong Jia Hu Hongyu Li Hongmei Tan Hongmei Tan Hongmei Tan α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis Frontiers in Cell and Developmental Biology lipid raft nicotine atherosclerosis α1-nAChRs NLRP3 inflammasome |
| title | α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis |
| title_full | α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis |
| title_fullStr | α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis |
| title_full_unstemmed | α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis |
| title_short | α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis |
| title_sort | α1 nachr mediated signaling through lipid raft is required for nicotine induced nlrp3 inflammasome activation and nicotine accelerated atherosclerosis |
| topic | lipid raft nicotine atherosclerosis α1-nAChRs NLRP3 inflammasome |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.724699/full |
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