title: Negative regulation of NLRP3 inflammasome by SIRT1 in vascular endothelial cells.
abstract: NLRP3 inflammasome not only functions as a critical effector in innate immunity, but also triggers the production of proinflammatory cytokines involved in inflammation-associated diseases. Sirtuin 1 (SIRT1) plays an important role in the regulation of cellular inflammation. However, whether the activation of NLRP3 inflammasome is regulated by SIRT1 remains unknown. In this study, we investigated the regulatory effect of SIRT1 on NLRP3 inflammasome and the underlying mechanisms. We found that lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-induced the activation of NLRP3 inflammasome in human umbilical vein endothelial cells (HUVECs). Activation of SIRT1 inhibited NLRP3 inflammasome activation and subsequent caspase-1 cleavage as well as interleukin (IL)-1β secretion, whereas SIRT1 knockdown obviously enhanced the activation of NLRP3 inflammasome in HUVECs. Importantly, gene silencing of SIRT1 abrogated the inhibitory effect of SIRT1 activator on NLRP3 inflammasome formation and IL-1β production in HUVECs stimulated with LPS plus ATP. Further study indicated that cluster of differentiation 40 (CD40) may be involved in the regulation of NLRP3 inflammasome by SIRT1. In vivo studies indicated that implantation of the periarterial carotid collar increased the arterial expression levels of CD40 and CD40 Ligand (CD40L), but inhibited arterial SIRT1 expression in the rabbits. Moreover, treatment with SIRT1 activator decreased CD40 and CD40L levels in collared arteries. Meanwhile, serum IL-1β level, the marker of inflammasome activation, was also inhibited by SIRT1 activation. Taken together, these findings revealed a novel regulatory mechanism of NLRP3 inflammasome by SIRT1, which may be related to suppression of CD40.
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China; Cardiovascular Research Center, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: He
authors.affiliation: Laboratory Animal Center, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Jing
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, China; Cardiovascular Research Center, Xi'an Jiaotong University, Health Science Center, Xi'an, China. Electronic address: linrong@mail.xjtu.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D023201:CD40 Ligand; D000255:Adenosine Triphosphate; D056564:Sirtuin 1
keywords: Endothelial cells; Inflammation; NLRP3 inflammasome; SIRT1