Abstract
Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived ...from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1β and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1β-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders.
Graphical Abstract
An accumulating body of evidence indicates that inflammation plays a crucial role in the pathophysiology of myocardial infarction (MI). Nucleotide-binding oligomerization domain-like receptor (NLR) ...family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates caspase-1 activation and the subsequent processing of the potent inflammatory cytokine interleukin (IL)-1β as well as triggering inflammatory cell death pyroptosis. We and other investigators demonstrated that deficiency of the NLRP3 inflammasome components reduces inflammation and improves cardiac dysfunction and remodeling in rodent models of MI. Therefore, the regulation of NLRP3 inflammasome has been regarded as a potential therapeutic target for MI. Furthermore, a recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial revealed the efficacy of IL-1β inhibition in preventing recurrent cardiovascular events in patients with MI. This review focuses on the role of NLRP3 inflammasome in the process of cardiac inflammation and remodeling after MI, and discusses its potential as a therapeutic target for the prevention and treatment of MI.
Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 ...activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.
Atherosclerosis and abdominal aortic aneurysm (AAA) are multifactorial diseases characterized by inflammatory cell infiltration, matrix degradation, and thrombosis in the arterial wall. Although ...there are some differences between atherosclerosis and AAA, inflammation is a prominent common feature of these disorders. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multiprotein complex that activates caspase-1 and regulates the release of proinflammatory cytokines interleukin (IL)-1β and IL-18, as well as the induction of lytic cell death, termed pyroptosis, thereby leading to inflammation. Previous experimental and clinical studies have demonstrated that inflammation in atherosclerosis and AAA is mediated primarily through the NLRP3 inflammasome. Furthermore, recent results of the Canakinumab Anti-inflammatory Thrombosis and Outcome Study (CANTOS) showed that IL-1β inhibition reduces systemic inflammation and prevents atherothrombotic events; this supports the concept that the NLRP3 inflammasome is a promising therapeutic target for cardiovascular diseases, including atherosclerosis and AAA. This review summarizes current knowledge with a focus on the role of the NLRP3 inflammasome in atherosclerosis and AAA, and discusses the prospects of NLRP3 inflammasome-targeted therapy.
Inflammasomes are multiple protein complexes that serve as molecular platforms to activate caspase-1 and regulate maturation of a potent proinfl ammatory cytokine, interleukin (IL)-1β, as well as ...proinfl ammatory cell death, pyroptosis. Although several types of inflammasomes have been reported so far, recent investigations indicate that the NLRP3 inflammasome recognizes non-microbial danger signals and leads to sterile inflammatory responses in various disease conditions. Sterile inflammatory responses are also implicated in the development of myocardial infarction (MI). In particular, IL-1β is an early and prominent mediator of inflammatory responses in MI, suggesting the pathophysiologic role of NLRP3 inflammasomes in MI. This review highlights the current state of knowledge regarding the role of NLRP3 inflammasomes in MI.
Inflammation plays a crucial role in the pathophysiology of myocardial infarction (MI). In particular, reperfusion caused by increased thrombolytic activity or revascularization therapy may restore ...the coronary blood flow and reduce the infarct size, but it also simultaneously enhances the inflammatory response and causes harmful effects on the myocardium—a process termed ischemia-reperfusion (I/R) injury. The inflammasome is a large multiprotein complex that is formed in the cytosol in response to danger signals; it drives the proinflammatory cytokine interleukin (IL)-1β. Increasing evidence indicates that the inflammasome is a key player in the disease processes of sterile inflammation. In particular, IL-1β is a prominent and early mediator of inflammation in I/R injury, suggesting the importance of the inflammasome in myocardial I/R injury. This article reviews the role of the inflammasome in the development of myocardial I/R injury and discusses the potential of the inflammasome as a novel therapeutic target for the treatment of myocardial I/R injury.
Myocardial infarction (MI) is accompanied by an inflammatory response, leading to the recruitment of leukocytes and subsequent myocardial injury and healing. Chemokines are potent chemoattractant ...cytokines that regulate leukocyte trafficking in inflammatory processes. Recent evidence indicates that chemokines play a role not only in leukocyte trafficking but also in angiogenesis and cardioprotection. In particular, stromal cell-derived factor-1α (SDF-1α) has generated considerable interest for its role in the pathophysiology of MI. This review will focus on the role of SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4; ie, the SDF-1/CXCR4 system) in the pathophysiology of MI and discuss their potential as therapeutic targets for MI. (Circ J 2010; 74: 418 - 423)
Inflammasome mechanisms are involved as some of the pathways of sterile inflammation. Inflammasomes are large multiprotein complexes in the cytosol and are a key system for the production of the ...pivotal inflammatory cytokines, interleukin (IL)‐1β and IL‐18, and inflammatory cell death called pyroptosis. Although a number of inflammasomes have been described, the nucleotide‐binding oligomerization domain‐, leucine‐rich repeat‐, and pyrin domain‐containing 3 (NLRP3) is the most extensively investigated inflammasome. Exogenous pathogen‐associated molecular patterns released during infection and endogenous crystalline danger/damage‐associated molecular patterns (DAMPs) are well‐known activators of NLRP3 inflammasomes. In addition, nanoparticle‐associated molecular patterns (NAMPs), which are mediated by synthetic materials, including nanomaterials and nanoparticles, are proposed to be new danger signals of NLRP3 inflammasomes. Importantly, NAMP‐ and DAMP‐triggered inflammation, a defining characteristic in inflammatory diseases, is termed as sterile inflammation because it occurs in the absence of foreign pathogens. This review focuses on the role of inflammasomes in exogenous NAMP‐ and endogenous crystalline DAMP‐mediated sterile inflammation. Moreover, many regulatory mechanisms have been identified to attenuate NLRP3 inflammasomes. Therefore, we also summarize endogenous negative regulators of NLRP3 inflammasome activation, particularly induced by NAMPs or crystalline DAMPs.
Inflammasome mechanisms are involved as some of the pathways of sterile inflammation. Nanoparticle‐associated molecular patterns (NAMPs), which are mediated by synthetic materials, including nanomaterials and nanoparticles, are proposed to be new danger signals of NLRP3 inflammasomes. NLRP3: nucleotide‐binding oligomerization domain‐, leucine‐rich repeat‐, and pyrin domain‐containing 3
Reproduction involves tightly regulated series of events and the immune system is involved in an array of reproductive processes. Disruption of well-controlled immune functions leads to infertility, ...placental inflammation, and numerous pregnancy complications, including preeclampsia (PE). Inflammasomes are involved in the process of pathogen clearance and sterile inflammation. They are large multi-protein complexes that are located in the cytosol and play key roles in the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and IL-18, and pyroptosis. The nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome is a key mediator of sterile inflammation induced by various types of damage-associated molecular patterns (DAMPs). Recent evidence indicates that the NLRP3 inflammasome is involved in pregnancy dysfunction, including PE. Many DAMPs (uric acid, palmitic acid, high-mobility group box 1, advanced glycation end products, extracellular vesicles, cell-free DNA, and free fatty acids) are increased and associated with pregnancy complications, especially PE. This review focuses on the role of the NLRP3 inflammasome in the pathophysiology of PE.
Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we ...investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors ferrostatin-1 (Fer-1) and Liproxstatin-1 and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (
-acetyl cysteine) and an NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI), but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1β, IL-6, TNF-α, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.
Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.
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