Integrin α5β1 Activates the NLRP3 Inflammasome by Direct Interaction with a Bacterial Surface Protein

Jun, Hye‐Kyoung; Lee, Sung-Hoon; Lee, Haeri; Choi, Bong‐Kyu

doi:10.1016/j.immuni.2012.05.002

Cited by 68 publications

(55 citation statements)

References 29 publications

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“…Integrin α5 activates the NLRP3 inflammasome in macrophages (23), and OS has been shown to induce NLRP3 inflammasome in ECs (20). Because OxLDL-induced NF-κB is α5-dependent (16) and NF-κB activation primes the induction of NLRP3 inflammasome (19), we reasoned that α5 activation is necessary for OS-induced inflammasome activation.…”

Section: Lipid Raft Translocation Of Integrin α5 Is Associated With Itsmentioning

confidence: 99%

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Sun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin α5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin α5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin α5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin α5 translocation and activation. In vivo, integrin α5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr −/− ) mice, and knockdown of integrin α5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin α5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin-and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction.integrin | lipid rafts | shear stress | proteomics | endothelial dysfunction S hear stress imposed on vascular endothelial cells (ECs) influences vascular phenotype and function. Atherosclerosis preferentially develops at branches and curvatures in the arterial tree where flow is disturbed. In contrast, pulsatile shear stress (PS) in the straight parts of the arteries is atheroprotective (1). At the cellular and molecular levels, disturbed flow pattern increases, while PS inhibits, the inflammatory response in ECs, including the expression of intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin 1β (IL-1β) (2). We found that integrins in ECs are shear stress-sensitive (3). Many subsequent studies demonstrated that integrin activation is essential for transmitting mechanical stimuli to intracellular biochemical pathways (4-6). Additionally, mounting evidence indicates that lipid raft microdomains, membrane receptors, cytoskeletal proteins, and extracellular matrices are linked to integrin activation in the context of mechanotransduction (7-11). However, the key mechanism underlying the differential effects of atheroprone versus atheroprotective flows in activating integrins that in turn induces inflammatory response in ECs remains to be elucidated.Lipid rafts are membrane microdomains that are enriched in cholesterol, sphingolipids, and a variety of signaling molecules, which function as cellular signaling platforms. These microdomains are more ordered and tightly packed than the surrounding membran...

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Section: Lipid Raft Translocation Of Integrin α5 Is Associated With Itsmentioning

confidence: 99%

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Sun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, extracellular ATP, released from cells stimulated with surface protein of the periodontopathogen Treponema denticola, induced K ? efflux through a cell membrane ATP receptor, P2X 7 , eventually leading to NLRP3 inflammasome activation (Jun et al 2012). These reports indicate that K ?…”

Section: Il-1b/il-18 Processing and Pyroptosis Inductionmentioning

confidence: 99%

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

Uchiyama

Tsutsui

2014

Arch. Immunol. Ther. Exp.

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“…Binding of ATP to its P 2 X 7 receptor triggers K + efflux and activates Nlrp3 mediated cytokine and caspase-1 processing, secretion and cell death ( Figure 2) [28,29]. More broadly, during infection dying cells are major sources of extracellular ATP in vivo [30].…”

Section: Signalling By Host-cell Surface Receptorsmentioning

confidence: 99%

Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens

Eldridge

Shenoy

2015

Current Opinion in Microbiology

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Integrin α5β1 Activates the NLRP3 Inflammasome by Direct Interaction with a Bacterial Surface Protein

Cited by 68 publications

References 29 publications

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens

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