NLRP3 inflammasome pathways in atherosclerosis

Baldrighi, Marta; Mallat, Ziad; Li, Xuan

doi:10.1016/j.atherosclerosis.2017.10.027

Cited by 168 publications

(120 citation statements)

References 149 publications

(177 reference statements)

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“…24,25 Previous studies suggested that several signaling pathways, including signals produced by inflammasomes and endoplasmic reticulum stress are involved in the occurrence and development of atherosclerosis. 14,26,27 However, the regulatory mechanism of atherosclerosis is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…12 NLRP3 inflammatory corpuscles can be activated by a variety of pathogenic microorganisms and risk signals, and participate in the occurrence of numerous human diseases. 13,14 There is also evidence that apoptosis signal-regulating kinase 1 (ASK1) is required for NLRP3 inflammasome activation. 15 However, it is not clear whether ox-LDL-mediated cholesterol efflux is associated with ERS, ASK1, and NLRP3 inflammatory corpuscles.…”

Section: Introductionmentioning

confidence: 99%

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<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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These authors contributed equally to this workObjective: This study was to investigate the mechanism of inflammatory pathology modification induced by ox-LDL in endothelial cells. Methodology: In this study, we firstly investigated the efflux of cholesterol of endothelial cells under the treatment of ox-LDL, and cell proliferation, ROS production, cell apoptosis was measured. Further, proteins of ASK1, NLRP3 inflammasomes and endoplasmic reticulum stress response were detected. Afterwards, ASK1 inhibitor (GS-4997) or endoplasmic reticulum stress (ERS) inhibitor (4-PBA) was used to measure the performance of endothelial cells. Results: In this study, endothelial cells were treated with ox-LDLs alone or in combination with a GS-4997 or 4-PBA. Results showed that ox-LDLs attenuated the efflux of cholesterol from endothelial cells in a dose-dependent manner. Ox-LDLs inhibited the proliferation of endothelial cells, and induced their apoptosis and production of reactive oxygen species (ROS). Additionally, ox-LDLs upregulated the levels of phosphorylated ASK1, ERS-related proteins (chop, p-PERK, GRP78, and p-IRE-1), and inflammation-associated proteins (NLRP3, IL-1β, and caspase 1) in endothelial cells. Moreover, we proved that GS-4997 could partly reverse ox-LDL-mediated cell proliferation, apoptosis, ROS production, and inflammation in endothelial cells, and increase cholesterol efflux. We also found that 4-PBA could attenuate the effects of ox-LDLs on endothelial cell cholesterol efflux, proliferation, apoptosis, ROS production, and inflammation. Conclusion: Our results suggest that cholesterol efflux from endothelial cells is reduced by ox-LDLs, and these reductions in cholesterol efflux are accompanied by increased NLRP3 inflammasome signaling, ASK1 and higher levels of endoplasmic reticulum stress. Our results suggest this axis as potential targets for treating atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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“…IL-1␤ plays a pivotal role in signaling of other inflammatory cytokines. Emerging evidence suggests a key role for the inflammasome in atherosclerotic disease progression (73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83) and in HIV-1 disease (47,(84)(85)(86)(87)(88)(89). Inflammasome activation requires two signals, one for priming (i.e., TLR signaling which results in transcriptional regulation) and then one for activation of inflammasome complex assembly.…”

Section: Discussionmentioning

confidence: 99%

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

Soare

Durham

Gopal

et al. 2019

J Virol

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HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. Anex vivohuman tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCEPatients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

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“…It was also shown that the NF‐κB pathway in the atherosclerotic lesions’ macrophages promoted monocytes infiltration and plaque development 83 . Moreover, oxidized mtDNA, which escaped degradation by autophagy, was reported to activate the NLRP3 inflammasome thus regulating the release of cytokines, such as IL‐1β and IL‐18 84,85 . In addition, mitochondrial dysfunction was also shown to affect the cholesterol efflux in macrophages 86 .…”

Section: Mitochondrial Dna Damage In Macrophagesmentioning

confidence: 99%

Lipid‐based gene delivery to macrophage mitochondria for atherosclerosis therapy

Zakirov

Zhang

Grechko

et al. 2020

Pharmacology Res & Perspec

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Atherosclerosis with associated cardiovascular diseases remains one of the main causes of disability and death worldwide, requiring development of new solutions for prevention and treatment. Macrophages are the key effectors of a series of events involved in atherogenesis, such as inflammation, plaque formation, and changes in lipid metabolism. Some of these events were shown to be associated with mitochondrial dysfunction and excessive mitochondrial DNA (mtDNA) damage. Moreover, macrophages represent a promising target for novel therapeutic approaches that are based on the expression of various receptors and nanoparticle uptake. Lipid‐based gene delivery to mitochondria is considered to be an interesting strategy for mtDNA damage correction. To date, several nanocarriers and their modifications have been developed that demonstrate high transfection efficiency and low cytotoxicity. This review discusses the possibilities of lipid‐based gene delivery to macrophage mitochondria for atherosclerosis therapy.

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NLRP3 inflammasome pathways in atherosclerosis

Cited by 168 publications

References 149 publications

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

Lipid‐based gene delivery to macrophage mitochondria for atherosclerosis therapy

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