The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 19(8), P. 477 - 489

Published: April 29, 2019

Language: Английский

---

Targeting the NLRP3 inflammasome in inflammatory diseases

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(8), P. 588 - 606

Published: July 20, 2018

Language: Английский

---

Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

The Journal of Experimental Medicine, Journal Year: 2017, Volume and Issue: 214(11), P. 3219 - 3238

Published: Oct. 11, 2017

The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety human diseases. A few compounds have developed to inhibit activation, but directly and specifically targeting are still not available, so it is unclear whether itself can be targeted prevent or treat Here we show that compound CY-09 blocks activation. binds ATP-binding motif NACHT domain inhibits ATPase activity, resulting suppression assembly Importantly, treatment with shows remarkable therapeutic effects on mouse models cryopyrin-associated autoinflammatory syndrome (CAPS) type 2 diabetes. Furthermore, active ex vivo for monocytes from healthy individuals synovial fluid cells patients gout. Thus, our results provide selective direct small-molecule inhibitor indicate combat NLRP3-driven

Language: Английский

---

Inflammasomes in neuroinflammatory and neurodegenerative diseases

EMBO Molecular Medicine, Journal Year: 2019, Volume and Issue: 11(6)

Published: April 23, 2019

Review23 April 2019Open Access Inflammasomes in neuroinflammatory and neurodegenerative diseases Sofie Voet VIB Center for Inflammation Research, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Search more papers by this author Sahana Srinivasan Mohamed Lamkanfi Corresponding Author [email protected] orcid.org/0000-0002-4898-7663 Internal Medicine, Janssen Immunosciences, World without Disease Accelerator, Pharmaceutical Companies Johnson & Johnson, Beerse, Geert van Loo orcid.org/0000-0002-8427-4775 Information Voet1,2, Srinivasan1,2, *,3,4 *,1,2 1VIB 2Department 3Department 4Janssen *Corresponding author. Tel: +32 14 605 343; E-mail: 93313761; Fax: 92217673; EMBO Mol Med (2019)11:e10248https://doi.org/10.15252/emmm.201810248 See the Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Neuroinflammation neurodegeneration often result from aberrant deposition aggregated host proteins, including amyloid-β, α-synuclein, prions, that can activate inflammasomes. function as intracellular sensors both microbial pathogens foreign well host-derived danger signals. Upon activation, they induce an innate immune response secreting inflammatory cytokines interleukin (IL)-1β IL-18, additionally inducing pyroptosis, a lytic cell death mode releases additional mediators. Microglia are prominent cells brain inflammasome activation. However, CNS-resident types astrocytes neurons, infiltrating myeloid periphery, express In review, we will discuss current understanding role inflammasomes common degenerative highlight inflammasome-targeted strategies may potentially treat these diseases. Blood–brain barrier (BBB) physiological between blood CNS parenchyma. The BBB is formed endothelial joined complex tight junctions coated basement membrane astrocytic end-feet, known glia limitans. Caspases family cysteine-dependent aspartate specific proteases play central inflammation programmed death. Cerebrospinal fluid (CSF) contained ventricles cranial spinal subarachnoid spaces. It provides mean transporting different molecules, cytokines, neurotransmitters, hormones, but also resides cells. macrophages non-parenchymal located meninges, choroid plexus, perivascular Creutzfeldt–Jakob disease fatal prion be sporadic, hereditary, or acquired. acquired form caused exposure misfolded scrapie PrP protein. Cuprizone-induced demyelination experimental model study local corpus callosum, which induced administration copper chelator cuprizone (bis(cyclohexanone)oxaldihydrazone) food mice during 5 weeks. Dopaminergic neurons dopamine-producing essential controlling key functions brain, voluntary movement, reward processing, mood, working memory. Encephalomyelitis general term describe cord. Autoimmune encephalomyelitis abnormal self-antigen. Experimental autoimmune (EAE) rodent MS. EAE actively peripheral immunization with myelin-specific proteins peptides combination adjuvant, passively transfer encephalitogenic T Familial Mediterranean Fever most monogenic autoinflammatory characterized periodic fevers childhood onset, frequently associated serositis joint pain. predominantly affects populations. Grand-mal seizures tonic-clonic seizures: loss consciousness violent muscle contractions. This seizure comes two phases: tonic phase followed clonic phase. brief features stiffening, while muscles go into rhythmic Induced pluripotent stem (iPSCs) generated genetic reprogramming adult somatic advantage over other not derived human embryo. Ischemic infarct interruption flow due occlusion cerebral vessel. Middle artery stroke involves permanent transient middle artery. one three arteries supply cerebrum. "filament model", suture filament (transiently) introduced internal carotid forwarded until tip occludes Neonatal-onset multisystem (NOMID) chronic infantile neurologic cutaneous articular (CINCA): severe cryopyrin-associated syndrome (CAPS). NOMID neonatal-onset skin lesions, aseptic meningitis, recurrent fever along symptoms. Sepsis life-threatening systemic (SIRS) body's infection. Spatial memory important cognitive allows us recall three-dimensional objects places. Steatohepatitis type fatty liver accumulation lipids infiltration hepatic Striata dopamine substantia nigra pars compacta project caudate putamen basal ganglia, together referred striatum. Substantia structure brainstem contains neurons. Introduction system rapid coordinated cellular defense aims eliminate threat posed sterile infectious insults. Recognition pathogenic agents mediated pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs) host- environment-derived danger-associated (DAMPs). nervous (CNS), PRRs primarily expressed microglia, astrocytes, macrophages, oligodendrocytes, repertoire (Lampron et al, 2013; Walsh 2014). either membrane-bound, case Toll-like (TLRs), signals extracellular environment endosome, intracellular, nucleotide-binding domain leucine-rich repeat-containing (NLRs) AIM2-like (ALRs). An subgroup cytosolic includes members NLR ALR families tripartite motif (TRIM) member pyrin critically contributes assembling so-called "inflammasomes". General concepts biology multiprotein complexes upon assembly pro-inflammatory caspase-1 (see Glossary) responsible maturation secretion IL-1β pyroptosis (Lamkanfi Dixit, 2014; Broz 2016). Briefly, inflammasome-inducing stimuli trigger oligomerization PRR recruitment pre-existing procaspase-1 zymogens complex, leading their proximity-induced autoactivation generate active caspase-1. Consequently, cleave biologically inactive pro-peptides pro-IL-1β pro-IL-18 mature then secreted cell. Next its pro-IL-18, death, early plasma rupture, thereby releasing soluble fraction fuels 2012, Central process executioner protein gasdermin D (GSDMD)—a substrate murine caspase-11, caspase-1, caspase-4, caspase-5—the amino-terminal cleavage oligomerizes perforates swelling osmotic lysis (Shi 2017) (Fig 1). Figure 1. Inflammasome activation signalingInflammasomes assemble stimulus-specific manner. Different DAMPs PAMPs able NLRP3, NLRP1b responds Bacillus anthracis lethal toxin, NLRC4 recognizes bacterial flagellin and/or III pathogens, AIM2 specifically activated dsDNA, inactivation RhoA toxins effector proteins. Activation NLRP3 two-step mechanism. priming signal detected membrane-bound PRRs, TLRs C-type lectin (CLRs) induces NF-κB-dependent transcription precursor protein, controls post-translational modifications license second necessary formation, depending on subsequent procaspase-1. Active cleaves forms IL-18 get secreted. addition, D, N-terminal fragment translocates pore formation pyroptotic contrast do need initial cytokine release. Download figure PowerPoint One way classify based receptor initiates signaling 2012). core components consist NLR, ALR, receptors, adaptor apoptosis-associated speck-like containing caspase (ASC) ASC composed (PYD) (CARD) links PYD CARD 2). Some inflammasomes, such NLRP1b, require directly recruit through respective CARDs, although under wild-type conditions does contribute optimal efficient (Broz 2010; Guey Van Opdenbosch Assembly requires detection signals: Murine Nlrp1b toxin (LeTx) (Boyden Dietrich, 2006); detects systems (T3SS) (Franchi 2006; Miao 2006, 2010); physically binds double-stranded DNA (dsDNA) (Hornung 2009); indirectly covalently inactivate small GTPase (Xu widely studied inflammasome, broad spectrum activating suite bacterial, fungal, viral PAMPs, ATP uric acid crystals, crystalline substances asbestos, silica, amyloid-β fibrils unique it process. A first signal, results transcriptional upregulation pro-IL-1β, highlighted mapped ubiquitin phosphorylation sites (Yang 2017). "activation" Besides canonical signaling, non-canonical pathway caspase-11 (or orthologs caspase-4 caspase-5) LPS, induction GSDMD release high mobility group box 1 (HMGB1) IL-1α Shi Apart NAIP/NLRC4 complexes, secondary messengers physical ligands bind await discovery. 2. Domain inflammasomesA subset NLRs ALRs have (NACHT/NBD), repeat (LRR) motifs, typically center carboxy terminus respectively. NACHT usually flanked domain, PYD, domains further sub-classification These allow complex. gene consists 22 34 members, many always clear 2012; addition NLR-containing DNA-binding HIN200 2009). Pyrin, TRIM20, B-boxes, coiled-coil whereas has C-terminal B30.2 domain. critical domains, latter being homotypic interaction PYD-containing sensor (NLRP3, AIM2). Procaspase-1 interactions direct indirect (via ASC) recruitment, resulting macromolecular aggregate, speck CNS, cognate initiate cascades neuronal injury (Allan 2005; Alboni 2010). Hence, increased levels observed infection, injury, (Heneka 2014, 2018). been shown participate processes cognition, learning, (Tsai, Pyroptosis inflammasome-driven pathology mediators DAMPs. Apoptosis necroptosis modes promote neuroinflammation degeneration several pathologies, multiple sclerosis, amyotrophic lateral Parkinson's disease, Alzheimer's (Zhang 2017; Yuan 2019). Although mainly attributed expression reported (Kaushal 2015), (Freeman 2017), (Kawana 2013), oligodendrocytes (Mckenzie 2018), (Gong 2018) 3). microglia still fragmentary vitro studies primary microglial lines, vivo transgenic knockout lack throughout body. More appropriate research tools CNS-specific targeting needed investigate relative contribution overall pathology. Furthermore, evidence patients relies higher transcript components. NF-κB responsive genes largely indicative ongoing rather than support engagement. We here review knowledge relevance pathologies 3 Table 1) emerging treatment diseases, Zika, HIV, West Nile virus, infections meningitis (Walsh Mamik Power, Heneka outside scope review. 3. diseaseInflammasomes acute (traumatic stroke), autoimmune-mediated (multiple sclerosis), (Alzheimer's disease). demonstrated types, CNS-infiltrating cells, macrophages. focused importance disorders. Overall, caspase-1-mediated cytokines. High considered crucial establishment environment, dysfunction eventually neurodegeneration. Overview described models Description Multiple sclerosis Cuprizone Administration callosum Stroke Permanent MCAO obtained using intraluminal Transient Intraluminal utilizes inserted interrupt duration afterward removed. Embolic uses autologous clot injected MCA occlude vessel Intracerebral hemorrhage (ICH) condition provoked injection arterial ganglia TBI SCI Controlled cortical impact (CCI) mechanical traumatic injury. Following craniotomy, CCI device mechanically transfers energy onto dura mater damaging cortex, sometimes subcortical structures Impact acceleration exposed skull covered steel disk weight dropped Contusion cord force applied electromagnetic weight-drop displace damage Alzheimer APP/PS1 Mouse expressing APP695 Swedish double mutation (K670N/M671L) mutant presenilin (PS1-dE9) 3xTgAD (K670N/M671L), PS1 M146V mutation, Tau P301L Tg2567 at β-secretase site 5xFAD APP PSEN1 transgenes total five AD-linked mutations: Florida (I716V), London (V717I) mutations APP, M146L L286V Amyotrophic TgSOD1-G93A G93A SOD1 hSOD1 G37R G85R Parkinson A53T alpha-synuclein. LPS-induced PD Injection LPS left 6-hydroxydopamine-induced 6-hydroxydopamine medial forebrain bundle MPTP-induced Intraperitoneal MPTP times 2-h intervals Prion Scrapie-infected homogenate strain 139A-infected intracerebral RML6 (passage 6 Rocky Mountain Laboratory mouse-adapted prions) Tg(CJD) (D177N/V128) Huntington R6/2 Transgenic exon huntingtin expanded CAG/polyglutamine (MS) CNS. MS compromised blood–brain leads periphery astrocyte inflammation, demyelination, (Baecher-Allan (Ransohoff, 2012), were (Sutton Gris Lévesque Most involvement shaped lymphocytes enter Caspase-1, upregulated mononuclear (PBMCs) cerebrospinal patients, inflammasome-activating (Inoue Shinohara, Moreover, was elevated demyelinating lesions (Voet recently proposed candidate biomarkers onset (Keane EAE-associated T-cell trafficking supported analysis (Furlan 1999; Inoue 2012a). pharmacological inhibitor MCC950/CRID3 suppress production attenuate severity (Coll 2015). Similarly, blockade protease activity Z-Val-Ala-DL-Asp-fluoromethylketone prodrug VX-765 reduced symptoms Mckenzie Interestingly, IFNβ, line MS, only effective inflammasome-dependent subtype, NLRP3-independent could reversed IFN-β therapy 2012b, provided border-associated anti-inflammatory A20 negatively regulate (Vande Walle 2014), deletion exacerbated hyperactivation resulted CNS-intrinsic another showed caspase-1- GSDMD-mediated myelin-forming cuprizone-induced NLRP3-deficient presented delayed oligodendrocyte loss, (Jha Additional similar observations mice, unlike protection had differential effect remyelination after treatment, demonstrating delay accelerated seen knockouts plays pathological stroke, identified So far, four distinct implicated viz. NLRP1, NLRC4, (Barrington Additionally, (MCAO), mouse (Kang 2000). Expression products IL-1β, postmortem tissue (Fann 2013). Studies inhibitors caspases caspase-1-deficient mice—that later (Kayagaki 2011)—showed (Friedlander 1997; Hara Schielke 1998; Rabuffetti 2000; Ross 2007). agreement, deficient exhibited dramatically ischemic volumes (Boutin 2001), IL-18-deficient did show (Wheeler 2003). deficiency MCC950/CRID3, intracerebroventricular siRNAs all ameliorated clinical outcomes (Ma Yang 2015; Ismael 2018b). Also, NLRC4- AIM2-deficient significantly smaller compared subjected tMCAO, strongly leukocyte (Denes Finally, peri-infarct zone rats revealed AIM2, (Lammerding 2016), consistent potential mu

Language: Английский

---

NLRP3 and pyroptosis blockers for treating inflammatory diseases

Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(8), P. 653 - 668

Published: May 3, 2022

The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases is an exciting drug target. Here, we review the molecular basis NLRP3 inhibition by drug-like small molecules under development novel therapeutics. We also summarize recent strategies to block pyroptosis approach suppress chronic inflammation. Major developments this area include elucidation mechanisms action (MoAs) which assembly gasdermin D (GSDMD)-induced pyroptosis. discuss status clinical trials using agents that specific components pathway, including their potential applications for treatment diseases.

Language: Английский

---

Tranilast directly targets NLRP 3 to treat inflammasome‐driven diseases

EMBO Molecular Medicine, Journal Year: 2018, Volume and Issue: 10(4)

Published: March 12, 2018

Research Article12 March 2018Open Access Source DataTransparent process Tranilast directly targets NLRP3 to treat inflammasome-driven diseases Yi Huang Institute of Immunology and the CAS Key Laboratory Innate Immunity Chronic Disease, Center for Excellence in Molecular Cell Sciences, Hefei National Physical Sciences at Microscale, University Science Technology China, Hefei, China Innovation Signaling Network, Search more papers by this author Hua Jiang Yun Chen State Cellular Stress Biology, School Life Xiamen University, Xiamen, Fujian, Xiaqiong Wang Yanqing Yang Department Clinical Laboratory, The First Affiliated Hospital Bengbu Medical College, Bengbu, Jinhui Tao Rheumatology & Immunology, Anhui, Xianming Deng Gaolin Liang Soft Matter Chemistry, Huafeng Zhang orcid.org/0000-0001-9923-7531 Wei Corresponding Author [email protected] orcid.org/0000-0001-8327-3079 Rongbin Zhou orcid.org/0000-0002-3351-6420 Information Huang1,2,‡, Jiang1,‡, Chen3, Wang1, Yang4, Tao5, Deng3, Liang6, Zhang1,2, *,1 *,1,2 1Institute 2Innovation 3State 4Department 5Department 6CAS ‡These authors contributed equally work *Corresponding author. Tel: +86-551-63600125; E-mail: +86-551-63600302; Fax: +86-551-63600831; EMBO Mol Med (2018)10:e8689https://doi.org/10.15252/emmm.201708689 PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract dysregulation inflammasome can cause uncontrolled inflammation drive development wide variety human diseases, but medications targeting are not available clinic. Here, we show that tranilast (TR), an old anti-allergic clinical drug, is direct inhibitor. TR inhibits activation macrophages, has no effects on AIM2 or NLRC4 activation. Mechanismly, binds NACHT domain suppresses assembly blocking oligomerization. In vivo experiments remarkable preventive therapeutic mouse models inflammasome-related gouty arthritis, cryopyrin-associated autoinflammatory syndromes, type 2 diabetes. Furthermore, active ex synovial fluid mononuclear cells from patients with gout. Thus, our study identifies drug as inhibitor provides potentially practical pharmacological approach treating NLRP3-driven diseases. Synopsis here reported beneficial By binding NLRP3, it its oligomerization subsequent assembly, caspase-1 IL-1β production. specifically both cells. complex formation. Introduction protein formed NOD-like receptor (NLR) family member adaptor ASC, (Martinon et al, 2009; Davis 2011; Jo 2016). A factors derived only pathogen, also environment host, activate result pyroptosis release secretion several proinflammatory cytokines, such IL-18 (Chen 2009). been be involved pathogenesis Mutations gene spontaneous associated syndromes (CAPS), which group rare, inherited, (Broderick 2015). addition, sense some host-derived "danger signals", monosodium urate crystals (MSU), cholesterol crystals, amyloid-β aggregates, unsaturated fatty acids, high glucose, ceramide, promote chronic contribute gout, atherosclerosis, neurodegenerative diabetes (T2D) 2006; Duewell 2010; Masters Wen Heneka 2012; Lamkanfi Dixit, 2012). NLPR3 regarded potential target treatment inflammatory recent years, few small-molecule compounds have shown inhibitory vitro, dimethyl sulfoxide (DMSO), 3,4-methylenedioxy-β-nitrostyrene, glyburide, parthenolide, sulforaphane, isoliquiritigenin, MCC950, β-hydroxybutyrate, flufenamic acid, mefenamic acid (Lamkanfi Juliana Yan 2013; Ahn 2014; He Honda Coll 2015; Youm Daniels 2016; Among them, tested animal Sulforaphane isoliquiritigenin alleviate high-fat diet (HFD)-induced metabolic disorders mice (Honda MCC950 β-hydroxybutyrate CAPS (Coll delay AD model (Daniels Dempsey 2017). Although these promising, none them urgent develop inhibitors safety trials. (N-[3′,4′-dimethoxycinnamoyl]-anthranilic TR) analog tryptophan metabolite effect homologous passive cutaneous anaphylaxis because inhibit IgE-induced histamine mast (Azuma 1976; Koda Platten 2005). Subsequently, clinically used bronchial asthma, atypical dermatitis, allergic conjunctivitis, hypertrophic scars (Darakhshan Pour, Moreover, relatively safe well tolerated most patients, doses up 600 mg/day over period months favorable against molecular mechanisms anti-inflammatory activity still unknown. study, showed bound inhibited More importantly, could prevent NLRP3-dependent was samples Results macrophages To confirm activation, first examined whether cleavage secretion. We indeed observed blocked nigericin-induced cleavage, secretion, (Fig 1A B, Appendix Fig S1A). It cytokine-induced NF-κB (Oh 2010), then via regulating expression NF-κB-dependent pro-IL-1β expression. When BMDMs were stimulated 30 min after 3-h LPS treatment, had LPS-induced expression, TNF-α, IL-6 production 1C D, S1B–D), suggesting TR-induced inhibition caused downregulation condition. contrast, when before production, minimal TNF-α (Appendix S1B–D). These results suggest suppress order clarify underlying inhibition, later experiments. confirmed THP-1 1E). Taken together, indicate Figure 1. A. Immunoblot analysis cleaved (p20) culture supernatants (SN) LPS-primed treated various (above lanes) nigericin, immunoblot precursors (pro-IL-1β) (pro-casp1) lysates those (Input). B–D. ELISA (B), (C) (D) nigericin. E. PMA-differentiated F. (100 μM) MSU, ATP, Alum, G. Alum. H. Pam3-primed cytosolic (cLPS), I. (cLPS). Data information: three independent biological duplicates each (B–D, G, I; mean s.e.m. n = 6) representative least (A, E, F, H). Statistics analyzed using unpaired Student's t-test: **P < 0.01, ***P 0.001. data online figure. 1 [emmm201708689-sup-0002-SDataFig1.pdf] Download figure PowerPoint addition activated pathogen-associated patterns (PAMPs) danger-associated (DAMPs), aluminum salts (Alum), (cLPS) (Davis Kayagaki 2011). determine common inflammasome, other agonists. Pretreatment triggered all agonists, cLPS 1F–I), similar Interestingly, block cLPS-induced gasdermin D (Gsdmd) pyroptosis, downstream caspase-11 non-canonical S1E F). potent broad canonical inflammasomes, inflammasome. Salmonella typhimurium (Salmonella) infection poly A:T transfection, respectively S2A B). demonstrate upstream signaling investigated how exert different effects, validated. proposed transient cation channel subfamily V (TRPV2) (Zhang 2012), TRPV2. knockdown TRPV2 S3A B), inhibition. Previous hematopoietic prostaglandin D2 synthase (HPGDS) (Ikai 1989), HPGDS S3C D). During ASC critical step (Lu Dick Consistent remarkably suppressed 2A). acts studied affected potassium efflux, event (Petrilli 2007; Munoz-Planillo 2013). Nigericin dramatically decrease intracellular potassium, S4A), efflux during Mitochondrial damage, represented mitochondria fission, clustering, ROS another (Zhou Nigericin-induced mitochondrial damage normal pretreated S4B), indicating does affect chloride Tang 2017), S4C), 2. nigericin min. Immunoprecipitation (IP) interaction endogenous NEK7 20 IP two [emmm201708689-sup-0003-SDataFig2.pdf] Next, assessed Recently, essential component NEK7–NLRP3 important (He Schmid-Burgk Shi previous studies, promoted between 2B). Another recruitment next determined impact NLRP3–ASC found pretreatment nigericin-treated 2C). blocks NLRP3-ASC formation Since formation, proteins. synthesized biotinylated (biotin-TR) affinity reagent incubated cell Compound pulled down streptavidin beads, proteins detected analysis. NEK-7, biotin-TR 3A interacts directly, purified recombinant 3C S5A), confirming NLRP3. innate immune sensors. Flag-tagged NOD1, NOD2, NLRP1, overexpressed HEK-293T cells, biotin-TR. 3D), contains functional domains, LRR, NACHT, PYD. responsible TR, 3E). 3. A, B. (A) THP-1. (B) Cells concentrations h, beads. C. Purified transfected NLRC4, NLRP3-LRR, NLPR3-NACHT, NLRP3-PYD constructs Flag-NLRP3 VSV-NLRP3 added 8 h post-transfection. SDD-AGE SDS–PAGE assay left 3 [emmm201708689-sup-0004-SDataFig3.pdf] oligomerization, NLRP3–NLRP3 interaction. then, co-immunoprecipitation performed. 3F). altered S5B). semi-denaturing detergent agarose gel electrophoresis (SDD–AGE) 3G), method detecting large oligomers studying prions (Alberti Hou ATPase (Duncan 2007), evaluated S5C), ATPase-independent manner. bind arthritis analyze vivo. Intraperitoneal injection MSU elicited peritonitis characterized massive neutrophil influx 2006). role efficiently MSU-induced 4A compared anti-inflammasome selective vitro around 400 times less than S6A), 5–10 S6B C). deposition major gout (McQueen Delivery joints leads inflammasome-dependent pathology (Reber 2014). this, induced acute joint swelling, alleviated Nlrp3 deficiency oral 4C).

Language: Английский

---

MCC950 closes the active conformation of NLRP3 to an inactive state

Nature Chemical Biology, Journal Year: 2019, Volume and Issue: 15(6), P. 560 - 564

Published: May 13, 2019

Language: Английский

---

Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Dec. 24, 2020

Abstract On 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by World Health Organization. As 4 August more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some develop respiratory failure which is leading cause death among COVID-19 patients. Endothelial cells with high levels angiotensin-converting enzyme 2 expression are major participants and regulators inflammatory reactions coagulation. Accumulating evidence suggests that endothelial activation dysfunction participate in pathogenesis altering integrity vessel barrier, promoting pro-coagulative state, inducing inflammation, even mediating leukocyte infiltration. This review describes proposed cellular molecular mechanisms during emphasizing principal mediators therapeutic implications.

Language: Английский

---

The NLRP3 inflammasome: Mechanism of action, role in disease and therapies

Molecular Aspects of Medicine, Journal Year: 2020, Volume and Issue: 76, P. 100889 - 100889

Published: Aug. 26, 2020

Language: Английский

---

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 10, 2022

The NLRP3 inflammasome is a multiprotein complex that plays pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs DAMPs, oligomerizes activates caspase-1 which initiates processing release of pro-inflammatory cytokines IL-1β IL-18. most extensively studied to date due its array activators aberrant several diseases. Studies using small molecules biologics targeting pathway have shown positive outcomes treating various disease pathologies blocking chronic inflammation. In this review, we discuss recent advances understanding mechanism, pathology, provide broad review therapeutics discovered target their challenges.

Language: Английский

---