Background
Nicotine 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
Conclusion
α1-nAChR-mediated signaling through lipid raft is required for NLRP3 inflammasome activation and pro-atherosclerotic property of nicotine.
Results
ApoE-/- 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.