NLRP3 inflammasome and its inhibitors: a review

“These endogenous non-coding RNAs are 20– 23 nt long and bind to the 3′ untranslated region (3′ UTR) of protein-coding mRNAs to regulate their translation (Bartel, 2009; Chen and Sun, 2013).”

“A newly identified PRR, first described in detail in 2002, is the inflammasome (Martinon et al., 2002; Gentile et al., 2015; Jorgensen and Miao, 2015; Sanders et al., 2015).”

“Formation of the inflammasome also triggers a process of inflammation-related cell death termed pyroptosis (Willingham et al., 2009; Schroder and Tschopp, 2010; Zhong et al., 2013a; Jorgensen and Miao, 2015).”

“…protect against disease and death, inappropriate activation of the NLRP3 inflammasome can contribute to the onset and progression of various diseases, particularly age-related diseases such as metabolic disorders and metabolic syndrome (Franceschi et al., 2000; Goldberg and Dixit, 2015).”

“…in macrophages and animal models have shown that oxidized low-density lipoprotein and cholesterol crystals trigger NLRP3 inflammasome activation (Duewell et al., 2010; Liu et al., Frontiers in Pharmacology | www.frontiersin.org 2 November 2015 | Volume 6 | Article 262 FIGURE 1 | Schematic…”

“…damage or dysfunction caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and…”

“…PAMPs or DAMPs are recognized by TLRs, leading to activation of nuclear factor kappa B (NF-κB)-mediated signaling, which in turn up-regulates transcription of inflammasome-related components, including inactive NLRP3, proIL-1β, and proIL18 (Bauernfeind et al., 2009; Franchi et al., 2012, 2014).”

“Coll et al. (2015) discovered that MCC950, a diarylsulfonylurea-containing compound known to inhibit caspase-1-dependent processing of IL-1β (Perregaux et al., 2001), also inhibits both canonical and non-canonical activation of the NLRP3 inflammasome.”

“Youm et al. (2015) discovered that the ketone metabolite β-hydroxybutyrate (BHB), but not acetoacetate or the shortchain fatty acids butyrate and acetate, reduced IL-1β, and IL-18 production by the NLRP3 inflammasome in human monocytes.”

“Type I IFNs are produced by specialized immune cells such as macrophages and DCs in response to extracellular stimuli such as bacteria and virus as well as various environmental irritants (Meylan et al., 2006).”

“Deficiency in microRNA-223 leads to neutrophilia, spontaneous lung inflammation, and increased susceptibility to endotoxin Frontiers in Pharmacology | www.frontiersin.org 5 November 2015 | Volume 6 | Article 262 challenge in mice (Johnnidis et al., 2008; Haneklaus et al., 2013).”

“A newly identified PRR, first described in detail in 2002, is the inflammasome (Martinon et al., 2002; Gentile et al., 2015; Jorgensen and Miao, 2015; Sanders et al., 2015).”

“…PAMPs or DAMPs are recognized by TLRs, leading to activation of nuclear factor kappa B (NF-κB)-mediated signaling, which in turn up-regulates transcription of inflammasome-related components, including inactive NLRP3, proIL-1β, and proIL18 (Bauernfeind et al., 2009; Franchi et al., 2012, 2014).”

“…studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin, 2014).”

“These include mitochondrial damage or dysfunction caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014;…”

“…caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of…”

“Pathogen-associated molecular patterns (PAMPs), which are antigens common to a given group of pathogens (Medzhitov, 2009; Abderrazak et al., 2015b), are normally recognized by at least three PRRs: Toll-like receptors (TLRs), C-type lectins (CTLs), and Galectins (Bourgeois and Kuchler, 2012;…”

“Activation of the NLRP3 inflammasome appears to occur in two steps (Zhong et al., 2013a; Sutterwala et al., 2014; Ozaki et al., 2015; Figure 1).”

“Polymorphism in the NLRP3 gene is linked to colitis severity and progression in patients (Villani et al., 2009; Lewis et al., 2011), and gain-of-function mutations in the NLRP3 gene that increase production and secretion of IL-1β and IL18 are associated with cryopyrin-associated periodic fever…”

“…models, studies have also defined a role for the NLRP3 inflammasome in the initiation and development of cerebral and myocardial ischemic diseases, including cerebral ischemia/stroke and myocardial ischemia (Sandanger et al., 2013; Marchetti et al., 2014; Hecker et al., 2015; Ito et al., 2015).”

“MicroRNA-223 binds to a conserved site in the 3′ UTR of the NLRP3 transcript, suppressing protein expression and thereby inhibiting NLRP3 inflammasome priming and IL-1β production (Bauernfeind et al., 2012; Haneklaus et al., 2012; Chen and Sun, 2013).”

“MicroRNA-223 binds to a conserved site in the 3′ UTR of the NLRP3 transcript, suppressing protein expression and thereby inhibiting NLRP3 inflammasome priming and IL-1β production (Bauernfeind et al., 2012; Haneklaus et al., 2012; Chen and Sun, 2013).”

“Baker et al. (2015) have shown that MCC950 inhibits LPS-induced production of IL-1β via a mechanism Smallmolecule inhibitor MCC950 Blocking apoptosis-associated speck-like protein (ASC) oligomerization, Inhibiting of canonical and non-canonical NLRP3 inflammasome;”

“…et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015; Liu et al.,…”

“Coll et al. (2015) further showed that MCC950 acts specifically on the NLRP3 inflammasome: it does not inhibit the activation of NLRP1, AIM2, or NLRC4 inflammasomes.”

“Formation of the inflammasome also triggers a process of inflammation-related cell death termed pyroptosis (Willingham et al., 2009; Schroder and Tschopp, 2010; Zhong et al., 2013a; Jorgensen and Miao, 2015).”

“Baker et al. (2015) have shown that MCC950 inhibits LPS-induced production of IL-1β via a mechanism Smallmolecule inhibitor MCC950 Blocking apoptosis-associated speck-like protein (ASC) oligomerization, Inhibiting of canonical and non-canonical NLRP3 inflammasome;”

“6:262. doi: 10.3389/fphar.2015.00262 NLRP3 inflammasome and its inhibitors: a review Bo-Zong Shao†, Zhe-Qi Xu†, Bin-Ze Han†, Ding-Feng Su and Chong Liu* Department of Pharmacology, Second Military Medical University, Shanghai, China Inflammasomes are newly recognized, vital players in innate…”

“However, how type I IFNs affect NLRP3 inflammasome and its production of IL-1β and IL-18 remains unclear (Guarda et al., 2011a), despite numerous studies aimed to improve IFN-based treatments of NLRP3 inflammasome-related diseases.”

“Formation of the inflammasome also triggers a process of inflammation-related cell death termed pyroptosis (Willingham et al., 2009; Schroder and Tschopp, 2010; Zhong et al., 2013a; Jorgensen and Miao, 2015).”

“…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014).”

“Consistent with this model, K+ efflux is a major activator of the NLRP3 inflammasome, while extracellular ATP and pore-forming toxins are the major triggers of IL-1β secretion by the inflammasome (Hari et al., 2014; Liu et al., 2014; Ketelut-Carneiro et al., 2015; Schmid-Burgk et al., 2015).”

“Formation of the inflammasome also triggers a process of inflammation-related cell death termed pyroptosis (Willingham et al., 2009; Schroder and Tschopp, 2010; Zhong et al., 2013a; Jorgensen and Miao, 2015).”

“…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014).”

“…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014).”

“…Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting…”

“…protect against disease and death, inappropriate activation of the NLRP3 inflammasome can contribute to the onset and progression of various diseases, particularly age-related diseases such as metabolic disorders and metabolic syndrome (Franceschi et al., 2000; Goldberg and Dixit, 2015).”

“Consistent with this idea, inhibiting the NLRP3 inflammasome reduces myocardial injury after ischemia-reperfusion in mice (Marchetti et al., 2014).”

“…studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin, 2014).”

“MCC950 inhibits both canonical and noncanonical inflammasome activation, while BHB affects only canonical activation.”

“…studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin, 2014).”

“Chang et al. (2015) showed that the plant polyphenolic compound resveratrol, known to induce autophagy, suppresses mitochondrial damage in macrophages and thereby inhibits NLRP3 inflammasome activation and NLRP3 inflammasomemediated IL-1β secretion and pyroptosis.”

“In macrophage and animal models of type II diabetes, hyperglycemia, and free fatty acids trigger inflammasome activation, which harms glucose metabolism and strengthens insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; Ruscitti et al., 2015).”

“For example, damage to NADPH oxidase and other oxidative systems by mitochondrial ROS can activate the inflammasome (van Bruggen et al., 2010; Crane et al., 2014; Lawlor and Vince, 2014; Rajanbabu et al., 2015).”

“For example, Patel et al. (2015) showed that genetic ablation of the NLRP3 inflammasome suppressor known as the inhibitor of κB kinase epsilon (IKBKE) enhanced the acute phase response and down-regulated cholesterol metabolism in cultured macrophages and hypercholesterolemic mice.”

“In macrophage and animal models of type II diabetes, hyperglycemia, and free fatty acids trigger inflammasome activation, which harms glucose metabolism and strengthens insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; Ruscitti et al., 2015).”

“…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014).”

“…PAMPs or DAMPs are recognized by TLRs, leading to activation of nuclear factor kappa B (NF-κB)-mediated signaling, which in turn up-regulates transcription of inflammasome-related components, including inactive NLRP3, proIL-1β, and proIL18 (Bauernfeind et al., 2009; Franchi et al., 2012, 2014).”

“Pathogen-associated molecular patterns (PAMPs), which are antigens common to a given group of pathogens (Medzhitov, 2009; Abderrazak et al., 2015b), are normally recognized by at least three PRRs: Toll-like receptors (TLRs), C-type lectins (CTLs), and Galectins (Bourgeois and Kuchler, 2012;…”

“…et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015; Liu et al., 2015).”

“Fluxes of intracellular and endoplasmic reticulum (ER)-related Ca2+ may also activate the NLRP3 inflammasome (Hussen et al., 2012; Zhong et al., 2013b; Shenderov et al., 2014).”

“Reducing the levels of these factors may be useful for treating inflammasome-related disease (Bandyopadhyay et al., 2013; Chen et al., 2015; Wang et al., 2015).”

“In macrophage and animal models of type II diabetes, hyperglycemia, and free fatty acids trigger inflammasome activation, which harms glucose metabolism and strengthens insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; Ruscitti et al., 2015).”

“Inhibiting IL-1 using specific blocking agents effectively reduces systemic inflammation in CAPS patients (Kuemmerle-Deschner, 2015; Yadlapati and Efthimiou, 2015).”

“In macrophage and animal models of uric acid accumulation, monosodium urate crystals activate the NLRP3 inflammasome, causing gout (Hari et al., 2014; Wang et al., 2014; Cleophas et al., 2015).”

“Studies in animal models suggest a similar picture in Alzheimer’s disease (Vajjhala et al., 2012; Schnaars et al., 2013; Cho et al., 2014) and obesity induced by a high-fat diet (Haneklaus and O’Neill, 2015; Zhang et al., 2015).”

“…et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015; Liu et al., 2015).”

“Increased production of IL-1β and IL-18 by the NLRP3 inflammasome contributes to atherosclerotic plaque progression and instability in atherosclerotic patients and animal models (Altaf et al., 2015; Patel et al., 2015; Peng et al., 2015).”

“In macrophage and animal models of type II diabetes, hyperglycemia, and free fatty acids trigger inflammasome activation, which harms glucose metabolism and strengthens insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; Ruscitti et al., 2015).”

“…characterized is the NLRP3 inflammasome, so named because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3” (Inoue and Shinohara, 2013b; Eigenbrod and Dalpke, 2015).”

“…in patients (Villani et al., 2009; Lewis et al., 2011), and gain-of-function mutations in the NLRP3 gene that increase production and secretion of IL-1β and IL18 are associated with cryopyrin-associated periodic fever syndrome (CAPS; Bozkurt et al., 2015; Carta et al., 2015; Zhou et al., 2015).”

“For example, damage to NADPH oxidase and other oxidative systems by mitochondrial ROS can activate the inflammasome (van Bruggen et al., 2010; Crane et al., 2014; Lawlor and Vince, 2014; Rajanbabu et al., 2015).”

“Pathogen-associated molecular patterns (PAMPs), which are antigens common to a given group of pathogens (Medzhitov, 2009; Abderrazak et al., 2015b), are normally recognized by at least three PRRs: Toll-like receptors (TLRs), C-type lectins (CTLs), and Galectins (Bourgeois and Kuchler, 2012; Dzopalic et al., 2012).”

“Malhotra et al. (2015) classified 97 patients with multiple sclerosis into those who responded to IFN-β therapy and those who did not, based on clinico-radiological criteria at 12 and 24 months of treatment.”

“Increased production of IL-1β and IL-18 by the NLRP3 inflammasome contributes to atherosclerotic plaque progression and instability in atherosclerotic patients and animal models (Altaf et al., 2015; Patel et al., 2015; Peng et al., 2015).”

“…a priming or initiating signal in which many PAMPs or DAMPs are recognized by TLRs, leading to activation of nuclear factor kappa B (NF-κB)-mediated signaling, which in turn up-regulates transcription of inflammasome-related components, including inactive NLRP3, proIL-1β, and proIL18…”

“…and others has demonstrated that NLRP3 inflammasome activation contributes to progression of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animal models (Ming et al., 2002; Jha et al., 2010; Lalor et al., 2011; Inoue et al., 2012a,b; Shao et al., 2014).”

“Consistent with this model, K+ efflux is a major activator of the NLRP3 inflammasome, while extracellular ATP and pore-forming toxins are the major triggers of IL-1β secretion by the inflammasome (Hari et al., 2014; Liu et al., 2014; Ketelut-Carneiro et al., 2015; Schmid-Burgk et al., 2015).”

“…et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015; Liu et al., 2015).”

“…characterized is the NLRP3 inflammasome, so named because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3” (Inoue and Shinohara, 2013b; Eigenbrod and Dalpke, 2015).”

“These include mitochondrial damage or dysfunction caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014;…”

“In the absence of immune activators, an internal interaction occurs between the NACHT domain and leucine-rich repeats (LRRs), suppressing the interaction between NLRP3 and ASC, thus preventing assembly of the inflammasome (Inoue and Shinohara, 2013a).”

“…models, studies have also defined a role for the NLRP3 inflammasome in the initiation and development of cerebral and myocardial ischemic diseases, including cerebral ischemia/stroke and myocardial ischemia (Sandanger et al., 2013; Marchetti et al., 2014; Hecker et al., 2015; Ito et al., 2015).”

“This triggers the transformation of procaspase-1 to caspase-1, as well as the production and secretion of mature IL-1β and IL-18 (Kim et al., 2015; Ozaki et al., 2015; Rabeony et al., 2015).”

“MicroRNA-223 binds to a conserved site in the 3′ UTR of the NLRP3 transcript, suppressing protein expression and thereby inhibiting NLRP3 inflammasome priming and IL-1β production (Bauernfeind et al., 2012; Haneklaus et al., 2012; Chen and Sun, 2013).”

“…studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin, 2014).”

“Formation of this complex triggers procaspase-1 self-cleavage, generating the active caspase-1 p10/p20 tetramer and inducing the conversion of proinflammatory cytokines interleukin (IL)1β and IL-18 from their immature “pro” forms to active forms that are secreted.”

“Reducing the levels of these factors may be useful for treating inflammasome-related disease (Bandyopadhyay et al., 2013; Chen et al., 2015; Wang et al., 2015).”

“Increased production of IL-1β and IL-18 by the NLRP3 inflammasome contributes to atherosclerotic plaque progression and instability in atherosclerotic patients and animal models (Altaf et al., 2015; Patel et al., 2015; Peng et al., 2015).”

“In macrophage and animal models of type II diabetes, hyperglycemia, and free fatty acids trigger inflammasome activation, which harms glucose metabolism and strengthens insulin resistance (Honda et al., 2014; Legrand-Poels et al., 2014; Ruscitti et al., 2015).”

“…et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of thioredoxin-interacting protein (TXNIP; Li et al., 2015; Liu et al., 2015).”

“This priming step is often studied in vitro using lipopolysaccharide (LPS; Park et al., 2015).”

“PRRs are expressed mainly in immune and inflammatory cells such as monocytes, macrophages, neutrophils, and dendritic cells (DCs) (Schroder and Tschopp, 2010; Fullard and O’Reilly, 2015).”

“For example, damage to NADPH oxidase and other oxidative systems by mitochondrial ROS can activate the inflammasome (van Bruggen et al., 2010; Crane et al., 2014; Lawlor and Vince, 2014; Rajanbabu et al., 2015).”

“They present antigens to the adaptive immune system to generate long-lasting protection (Alexandre et al., 2014).”

“Polymorphism in the NLRP3 gene is linked to colitis severity and progression in patients (Villani et al., 2009; Lewis et al., 2011), and gain-of-function mutations in the NLRP3 gene that increase production and secretion of IL-1β and IL18 are associated with cryopyrin-associated periodic fever…”

“…doi: 10.3389/fphar.2015.00262 NLRP3 inflammasome and its inhibitors: a review Bo-Zong Shao†, Zhe-Qi Xu†, Bin-Ze Han†, Ding-Feng Su and Chong Liu* Department of Pharmacology, Second Military Medical University, Shanghai, China Inflammasomes are newly recognized, vital players in innate immunity.”

“The innate immune system is evolutionarily conserved across vertebrates and invertebrates, which means that both human and animal studies can provide valuable insights into innate immunity (Dai et al., 2015).”

“For example, damage to NADPH oxidase and other oxidative systems by mitochondrial ROS can activate the inflammasome (van Bruggen et al., 2010; Crane et al., 2014; Lawlor and Vince, 2014; Rajanbabu et al., 2015).”

“A newly identified PRR, first described in detail in 2002, is the inflammasome (Martinon et al., 2002; Gentile et al., 2015; Jorgensen and Miao, 2015; Sanders et al., 2015).”

“For example, Patel et al. (2015) showed that genetic ablation of the NLRP3 inflammasome suppressor known as the inhibitor of κB kinase epsilon (IKBKE) enhanced the acute phase response and down-regulated cholesterol metabolism in cultured macrophages and hypercholesterolemic mice.”

“Studies in animal models suggest a similar picture in Alzheimer’s disease (Vajjhala et al., 2012; Schnaars et al., 2013; Cho et al., 2014) and obesity induced by a high-fat diet (Haneklaus and O’Neill, 2015; Zhang et al., 2015).”

“Nevertheless both inhibitors represent a significant advance toward developing therapies that target IL-1β and IL-18 production by the NLRP3 inflammasome in various diseases (Netea and Joosten, 2015).”

“…studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency (Shido et al., 1989; Johnson et al., 2007; McGettrick and O’Neill, 2013; Mercken et al., 2013; Newman and Verdin, 2014).”

“Inhibiting IL-1 using specific blocking agents effectively reduces systemic inflammation in CAPS patients (Kuemmerle-Deschner, 2015; Yadlapati and Efthimiou, 2015).”

“Fluxes of intracellular and endoplasmic reticulum (ER)-related Ca2+ may also activate the NLRP3 inflammasome (Hussen et al., 2012; Zhong et al., 2013b; Shenderov et al., 2014).”

“Studies in macrophages and mouse models of colitis have linked abnormal NLRP3 inflammasome activation with inflammatory bowel disease, including ulcerative colitis and Crohn’s disease (Cheng et al., 2015; Guo et al., 2015; Sun et al., 2015).”

“…in patients (Villani et al., 2009; Lewis et al., 2011), and gain-of-function mutations in the NLRP3 gene that increase production and secretion of IL-1β and IL18 are associated with cryopyrin-associated periodic fever syndrome (CAPS; Bozkurt et al., 2015; Carta et al., 2015; Zhou et al., 2015).”

“This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of mature proinflammatory IL1β and IL-18.(107) The transcription factor NF-κB, which is chronically active in mononuclear cells from diabetic patients and in vascular endothelial cells of dia…”

“Additionally, it has been demonstrated that NF-jB–mediated signaling is also involved in the NLRP3 inflammasome activation by regulating the transcription of inflammasome-related components, including inactive NLRP3, pro-IL-1b, and pro-IL-18.(46) More recently, TMAO has been found to induce phosphorylation of the NF-j…”

“NLRs form a large protein family of intracellular sensors, the members of which share a conserved central nucleotidebinding, oligomerization domain (NOD), a leucine-rich repeat (LRR) region, and a variable N-terminal effector domain [14, 15].”

“In accord with this, PAMPs and DAMPs as well as the NLRP3 agonist ATP, activate the production of ROS that trigger the NLRP3 complex formation through damage to NADPH oxidase and other mitochondrial oxidative systems [39, 47, 48].”

“On the other hand, a diet that increased ketone metabolite β-hydroxybutyrate levels inhibited NLRP3 activity during intense exercise (Shao et al., 2015; Youm et al., 2015).”

“IFN β therapy appears to be an effective treatment to downregulate NLRP3 inflammasomes.(261) Several other treatments that target the NLRP3 inflammasome, some of which are currently available, are reviewed by Shao et al.”

“inflammasome contains an adapter protein, apoptosis-associated speck-like protein and procaspase-1 [38].”

“There are many excellent recent reviews highlighting the discovery and novel mechanistic understanding of small-molecule inhibitors for NLRs and caspases, and the preclinical/ clinical impact of targeting the inflammasome products IL-1β and IL-18 in disease [138, 139, 140, 141, 142] .”

“inflammatory cytokines maturation [13, 14].”

“To further confirm whether dual MN patch–mediated treatment could inhibit the activation of the NLRP3 inflammasome in vivo, we detected the expression of IL-1, pro–IL-1, IL-18, and NLRP3 in skin homogenates (Fig.”

“Thus, a few compounds showing inhibitory activity for NLRP3 have emerged as a therapy for autoimmune diseases (Shao et al., 2015; Perera et al., 2017).”

“Initiation of transcription and translation of the pro-form for these two cytokines is due to for example Toll-like receptor (TLR) activity, but it is the second signal from P2X7 that matures and releases these cytokines (Shao et al., 2015).”

“…in DCM, which will elucidate the significance of NLRP3 inflamamsome as the molecular marker of DCM. NLRP3 INFLAMMASOME BIOLOGY NLRP3 inflammasome consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1 (Shao et al., 2015).”

“This complex comprises NLRP3, apoptosis-related speck-like protein containing (ASC) a caspase recruitment domain (CARD) and procaspase-1 [20], suggesting that pyroptosis may be closely involved in the pathological changes associated with OA.”

“Several studies have successfully sought to identify NLRP3-specific inhibitors [31], although like NLRP3 activation itself, their mechanisms of action remain unknown.”

“This results in maturation and secretion of some interleukins including IL-1β and IL-18, as well as other mediators of soluble inflammation which are all of potent pro-inflammatory activities [6, 20, 21].”

“The activated NLRP3 inflammasome triggers pro-caspase-1 self-cleavage and this complex releases cleaved caspase-1 into the cytosol, which induces the conversion of IL-1β from its immature ‘‘pro’’ forms to an active form, which is secreted (Willingham et al., 2009; Shao et al., 2015).”

“However, considering that the use of MCC950 to block the activation of the NLRP3 inflammasome only reduced the secretion of inflammatory factors [37], consequently, the most direct effect was observed when mice were treated with MCC950, which reduced the secretion of IL-1β.”

“This second step is controlled by various signals including efflux (such as K + efflux through the purogenic P2X7-receptor), crystals (such as urate, silica, asbestos, amyloid-β, and alum) and mitochondrial components (as discussed below) (35).”

“The dysregulation of NLRP3 inflammasome has been shown to be related with a variety of diseases, including multiple sclerosis, diabetes, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease, and many other autoimmune diseases [26].”

“…the IL1B signature in PPMS patients were due to increased pre-existing NLRP3 protein expression levels secondary to elevated mRNA expression levels and/or augmented signalling through the NF-j B pathway, which is known to upregulate the transcription of inflammasome components (Shao et al. , 2015).”

“Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a cytoplasmic multiprotein complex of the innate immune system that can trigger a series of immune-inflammatory reactions (Shao et al., 2015).”

“The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, as well as other inflammatory diseases [23].”

“inflammasome inhibitors, MCC950 blocks ASC oligomerization to inhibit canonical and non-canonical NLRP3 inflammasome activation rather than by reducing NLRP3 protein expression [35].”

“The second signal results in the assembly of the NLRP3 inflammasome, caspase-1 activation, and IL-1β secretion [13].”

“*P .05, **P .01 vs CMS. inflammasome to induce caspase-1 cleavage, leading to the maturation of the proinflammatory cytokines IL-1β and IL-18 (Schroder and Tschopp, 2014).”

“For example, small molecule inhibitors targeting NLRP3 directly are one promising drug development [115].”

“For example, MCC950, the NLRP3 Inhibitor, has antiinflammatory and anti-senescence effects on some chronic diseases such as Alzheimer’s disease.(89) In a recent study, Ni et al found that the NLRP3 protein was upregulated in the human and mouse OA cartilage and the intra-articular administration of MCC950 could postpo…”

“The NLRP3 inflammasome results from the assembly of NLR family pyrin domain containing 3 (NLRP3), apoptosis‐asso‐ ciated speck‐like protein (ASC) and caspase‐1 (14), and promotes the secretion of inflammatory cytokines, influencing the pathophysiology of epilepsy (14).”

“Recent findings suggest that NLRP3 inflammasome activation may play an important role in the progression of various metabolic disorders, such as type 2 diabetes and atherosclerosis and NLRP3 pathways have been associated with several autoimmune and autoinflammatory disorders including gout, familial Mediterranean feve…”

“MCC950 is an NLRP3 inflammasome-specific inhibitor that inhibits NLRP3 activity by blocking ASC oligomerization and NLRP3 ATP hydrolysis (128).”

“The activation of proinflammatory NLRs, such as NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NAIP has been reported to result in the formation of inflammasome and production of potent inflammatory cytokines, such as IL-1β and IL-18 (78, 79).”

“NOD1 and NOD2) present within the cytoplasm (Figure 1) [5].”

“a) Potassium efflux, considered the most crucial; b) ROS induced by DAMPs or PAMPs; c) Cathepsin B released by lysosomes (Shao et al., 2015).”