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Cellular Models and Assays to Study NLRP3 Inflammasome Biology International Journal of Molecular Sciences Review Cellular Models and Assays to Study NLRP3 Inflammasome Biology 1 1, 1, 2 2,3 Giovanni Zito , Marco Buscetta y, Maura Cimino y, Paola Dino , Fabio Bucchieri and Chiara Cipollina 1,3,* 1 Fondazione Ri.MED, via Bandiera 11, 90133 Palermo, Italy; [email protected] (G.Z.); [email protected] (M.B.); [email protected] (M.C.) 2 Dipartimento di Biomedicina Sperimentale, Neuroscenze e Diagnostica Avanzata (Bi.N.D.), University of Palermo, via del Vespro 129, 90127 Palermo, Italy; [email protected] (P.D.); [email protected] (F.B.) 3 Istituto per la Ricerca e l’Innovazione Biomedica-Consiglio Nazionale delle Ricerche, via Ugo la Malfa 153, 90146 Palermo, Italy * Correspondence: [email protected]; Tel.: +39-091-6809191; Fax: +39-091-6809122 These authors contributed equally to this work. y Received: 19 May 2020; Accepted: 12 June 2020; Published: 16 June 2020 Abstract: The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action. Keywords: NLRP3; inflammasome; NLRP3 inhibitors; cell models; biochemical assays; biophysical assays; read-outs 1. Introduction Innate immunity represents the first line of defense against invading pathogens or endogenous stress signals. Innate immune responses are mediated by a series of biological processes that have the common aim of restoring tissue homeostasis. The inflammatory cascade is triggered by the recognition of pathogen-associated molecular pattern (PAMP) and danger-associated molecular pattern (DAMP) by pattern recognition receptors (PRRs) that are mainly expressed by immune cells, such as macrophages. Among PRR, the nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) family is able to recognize cytosolic DAMPs/PAMPs. NLRs are expressed in the cytosol of myeloid-derived immune cells as well as in other cell types, such as epithelial and endothelial cells. Among NLRs, NLRP3 is one of the most studied and represents an attractive therapeutic target for several chronic diseases. Upon activation, NLRP3 assembles into a multimeric inflammasome complex comprising a core unit containing the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and Int. J. Mol. Sci. 2020, 21, 4294; doi:10.3390/ijms21124294 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 4294 2 of 19 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 19 cases,the eff NIMA-relatedector pro-caspase-1. kinase In 7 specific(NEK7) cases,binding NIMA-related to NLRP3 appears kinase to 7 (NEK7)be required binding for NLRP3 to NLRP3 activation appears [1].to be Following required forinflammasome NLRP3 activation assembly, [1]. Following autocatalytic inflammasome activation of assembly, caspase-1 autocatalytic takes place, activation triggering of thecaspase-1 cleavage takes and place, release triggering of the pro-inflammatory the cleavage and cytokines release of IL-1 theβ pro-inflammatory and IL-18, and the cytokines processing IL-1 ofβ gasdermin-Dand IL-18, and (GSDMD), the processing which ofleads gasdermin-D to a form (GSDMD), of programmed which leadsinflammatory to a form cell of programmeddeath called pyroptosis.inflammatory cell death called pyroptosis. GainGain of of function function mutations mutations of of NLRP3 NLRP3 genes genes cause cause cryopyrin cryopyrin associated associated periodic periodic syndromes syndromes (CAPS)(CAPS) [2]. [2]. Over-activation Over-activation of of NLRP3 NLRP3 has has been been as associatedsociated with with many many chronic chronic inflammatory inflammatory diseases diseases suchsuch as Alzheimer’s diseasedisease [ 3[3],], Parkinson’s Parkinson’s disease disease [4 ],[4], multiple multiple sclerosis sclerosis [5], [5], metabolic metabolic disease disease and typeand type2 diabetes 2 diabetes mellitus mellitus (T2D), (T2D), atherosclerosis atherosclerosis [6], gout [6], [gout7], osteoarthritis [7], osteoarthritis [8], and [8], rheumatoid and rheumatoid arthritis arthritis [6,7,9]. [6,7,9].These evidences,These evidences, combined combined with genetic with proofsgenetic that proofs knocking that knocking out NLRP3 out restores NLRP3 healthy restores phenotype healthy phenotypein several diseasein several models disease and models the finding and thatthe downregulationfinding that downregulation of NLRP3 has of minor NLRP3 impact has onminor host impactdefense on mechanisms host defense [10 ]mechanisms make NLRP3 [10] an attractivemake NL therapeuticRP3 an attractive target. Althoughtherapeutic numerous target. Although factors of numerousNLRP3 biology factors have of NLRP3 been extensively biology have described, been ex manytensively aspects described, remain subjectmany aspects of debate. remain This subject review ofaims debate. to summarize This review recent aims findings to summarize in NLRP3 recent inflammasome findings in biologyNLRP3 withinflammasome a special focus biology on the with tools a special(cellular focus models on the and tools assays) (cellular developed models so farand to assays) study inflammasomedeveloped so far activation to study and inflammasome the action of activationsmall molecule and the inhibitors. action of small molecule inhibitors. 1.1.1.1. Mechanisms Mechanisms of of NLRP3 NLRP3 Activation Activation ThreeThree pathways pathways of of NLRP3 NLRP3 inflammasome inflammasome activation activation have have so far so been far been described: described: canonical, canonical, non- canonicalnon-canonical and alternative and alternative pathway pathway (Figure (Figure 1). 1). Figure 1. Schematic representation of the mechanisms regulating inflammasome activation in Figurecanonical, 1. non-canonicalSchematic representation and alternative of pathway.the mechanisms Abbreviations: regulating PAMP, inflammasome pathogen-associate activation molecular in canonical,pattern; TLRs, non-canonical toll-like receptors; and alte NF-kB,rnative nuclearpathway. factor Abbreviations: kappa-light-chain-enhancer PAMP, pathogen-associate of activated molecularB cells; PTM, pattern; post-translational TLRs, toll-like modifications; receptors; NF-k eATP,B, nuclear extracellular factor adenosinekappa-light-chain-enhancer triphosphate; mROS, of activatedmitochondrial B cells; reactive PTM, post-trans oxygen species;lational ASC,modifications; apoptosis-associated eATP, extracellular speck-like adenosine protein triphosphate; containing a mROS,CARD; IL,mitochondrial interleukin; GSDMD,reactive gasderminoxygen species; D; iLPS, AS intracellularC, apoptosis-associated LPS; TRIF, TIR-domain-containing speck-like protein containingadapter-inducing a CARD; interferon- IL, interleukin;β; RIPK, GSDMD, receptor-interacting gasdermin serineD; iLPS,/threonine-protein intracellular LPS; kinase TRIF, 1; FADD, TIR- domain-containingFas-associated protein adapter-inducing with death domain; interferon- NLRP3,β NLR; RIPK, family receptor-interac pyrin domainting containing serine/threonine- 3. protein kinase 1; FADD, Fas-associated protein with death domain; NLRP3, NLR family pyrin domain containingCanonical 3. activation is the classical two-step model where two signals are required for optimal activation of the NLRP3 inflammasome. Signal 1, or priming, requires binding of toll-like receptors (TLRs)Canonical with pathogen-associated activation is the classical molecular two-step patterns model (PAMPs) where such two as signals lipopolysaccharide are required (LPS).for optimal Signal activation1 induces theof the transcriptional NLRP3 inflammasome. up-regulation Signal of NLRP3, 1, or priming, pro-IL-1 βrequires, and pro-IL-18 binding viaof toll-like Nuclear receptors Factor-kB (TLRs)(NF-kB) with activation pathogen-associated [11,12]. Growing molecular evidence indicatespatterns that(PAMPs) Signal 1such promotes as lipopolysaccharide more than transcriptional (LPS). Signalup-regulation, 1 induces as the it induces transcriptional a number up-regulation of post-translational of NLRP3, modifications pro-IL-1β, and (PTMs) pro-IL-18 that allow via Nuclear NLRP3 Factor-kBto switch into(NF-kB) its active activation conformation [11,12]. Growing [13]. Signal eviden 2 isce triggered indicates by that diverse Signal stimuli 1 promotes including more PAMPs, than transcriptional up-regulation, as it induces a number of post-translational modifications (PTMs) that Int. J. Mol. Sci. 2020, 21, 4294 3 of 19 DAMPs, and particulate matter which NLRP3 “senses”
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