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NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases molecules Review NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases Eleonora Mezzaroma 1,2, Antonio Abbate 1 and Stefano Toldo 1,* 1 VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA; [email protected] (E.M.); [email protected] (A.A.) 2 Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, VA 23298, USA * Correspondence: [email protected]; Tel.: +1-804-628-3396 Abstract: Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)- containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases. Keywords: NLRP3; inflammasome; caspase-1; ASC; IL-1; IL-18; cardiovascular disease; ischemia; heart failure; inhibitor Citation: Mezzaroma, E.; Abbate, A.; 1. Introduction Toldo, S. NLRP3 Inflammasome The innate immune system comprehends a genetically coded and inherited set of Inhibitors in Cardiovascular Diseases. receptors that recognize pathogens based on the ligand chemical property. These receptors Molecules 2021, 26, 976. https:// are therefore defined as “pattern recognition receptors” (PRRs) [1]. Several unrelated doi.org/10.3390/molecules26040976 agonists sharing similar chemical properties can bind to the same PRR. Altogether, these agonists are referred to as “pathogen-associated molecular patterns” (PAMPs) [1]. During Academic Editor: Massimo Bertinaria an infection, the activation of PRRs mediates the transcription and secretion of chemokines and cytokines, leading to activation and reprogramming of myeloid and lymphoid cells [2]. Received: 19 December 2020 Due to the low selectivity of some PRRs, self-molecules released by damaged or stressed Accepted: 20 January 2021 Published: 12 February 2021 cells can activate PRRs in the absence of an ongoing infection. These molecules are alto- gether defined as “damage-associated molecular patterns” (DAMPs) and include several Publisher’s Note: MDPI stays neutral intracellular proteins that, when released outside the cell, act as “alarmins” (Figure1)[ 1,2]. with regard to jurisdictional claims in The production of DAMPs and the activation of PRRs following cell or tissue damage published maps and institutional affil- coordinate the process of damage resolution and healing [3]. Virtually every human chronic iations. disease is associated with the activation of a set of PRRs [4–6]. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are PRRs [7]. Several of the proteins in the NLR family form multiprotein complexes defined as “in- flammasomes”, which lead to the activation of a pro-inflammatory enzyme caspase-1 (or caspase-11 in mice and caspase-4 and -5 in humans) and the secretion of cytokines of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the interleukin (IL)-1 family [7]. NACHT, leucine-rich repeat (LRR), and pyrin domain This article is an open access article (PYD)-containing protein 3 (NLRP3) is the most studied inflammasome due to its patho- distributed under the terms and physiological activation in infectious, rheumatologic, and chronic diseases [8]. Moreover, conditions of the Creative Commons the NLRP3 inflammasome promotes tissue damage following acute organ injury, such as Attribution (CC BY) license (https:// acute myocardial infarction (AMI) [9]. NLRP3 is a sensor of damage [7]. When active, creativecommons.org/licenses/by/ it transforms the cell into a pro-inflammatory factory of cytokines and/or leads to cell 4.0/). death (Figure1). Molecules 2021, 26, 976. https://doi.org/10.3390/molecules26040976 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 976 2 of 19 Molecules 2021, 26, 976 transforms the cell into a pro-inflammatory factory of cytokines and/or leads to cell death2 of 19 (Figure 1). Cell/Tissue Injury Release of DAMPs/Alarmins PRRs activation (TLRs, NLRs) NLRP3 inflammasome activation Amplification of inflammation and/or cell death Figure 1. Schematic representation of the critical steps that lead from cellular injury to the inflamma- Figure 1. Schematic representation of the critical steps that lead from cellular injury to the inflam- matorytory response. DAMPs, damage associated molecular patterns; PRRs, pattern recognitionrecognition receptors;recep- tors;TLRs, TLRs, Toll-like Toll-like receptors; receptors; NLRs, NLRs, Nod-like Nod-like receptors;receptors; NLRP3,NLRP3, NACHT, leucine-rich repeat repeat (LRR), (LRR),and and pyrin pyrin domain domain (PYD)-containing (PYD)-containing protein protein 3. 3. 1.1. PRRs That Regulate Inflammasome Formation 1.1. PRRs That Regulate Inflammasome Formation NLRs include several families of cytoplasmic proteins, including NOD receptors; NLRs include several families of cytoplasmic proteins, including NOD receptors; NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing proteins (NL- NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing proteins RPs); and NACHT, leucine-rich repeat (LRR), and caspase recruitment domain (CARD)- (NLRPs);containing and proteinsNACHT, (NLRCs) leucine-rich [10,11 ].repeat Some NLRs(LRR), form and inflammasomes,caspase recruitment while domain others are (CARD)-containingsignaling receptors. proteins Nod1 and(NLRCs) Nod2 are[10,11]. solely Some involved NLRs in inflammatoryform inflammasomes, signaling while through othersmitogen-activated are signaling receptors. protein kinases Nod1 and (MAPKs) Nod2 are and solely nuclear involved factor kappain inflammatoryB (NF-κB) [sig-12,13]. nalingNLRPs through and NLRCsmitogen-activated include some protei of then kinases most widely (MAPKs) studied and inflammasomenuclear factor kappa receptors, B (NF-suchκB) as[12,13]. NLRP3, NLRPs NLRP1, and and NLRCs NLRC4 include [11,12 ].some NLRP3 of the has most been widely extensively studied studied inflam- in the masomecardiovascular receptors, system such as [9 NLRP3,,11,14]. NLRP1NLRP1, hasand been NLRC4 shown [11,12]. to have NLRP3 a role has in been the responseexten- sivelyto viral studied and in bacterial the cardiovascular infections but system to be less[9,11,14]. involved NLRP1 in sterile has been inflammation shown to duehave to a in- rolejury in the [10, 12response]. However, to viral a recent and bacterial study has infe foundctions a homeostatic but to be less role involved of NLRP1 in in sterile controlling in- flammationbaseline levels due to of injury IL-18 [[10,12].15]. In mice, However, NLRP1 a deletion,recent study like IL-18has found deletion, a homeostatic promotes overeat- role of NLRP1ing, obesity, in controlling and glucose baseline intolerance levels of [15 IL-18]. NLRC4 [15]. In is mice, highly NLRP1 expressed deletion, in the like intestinal IL-18 deletion,epithelium promotes and isovereating, widely investigated obesity, and in theglucose interaction intolerance with intestinal[15]. NLRC4 bacterial is highly flora ex- [16]. pressedThe in the IFI20X/IFI16 intestinal epithelium family includes and theis widely non-NLR investigated inflammasome in the forming interaction receptor with absent in- testinalin melanoma bacterial 2flora (AIM2) [16]. [ 17]. AIM2 is an intracellular PRR that identifies double-stranded DNA.The IFI20X/IFI16 When the DNA family of replicatingincludes the pathogens non-NLR (e.g., inflammasome viruses and forming bacteria) receptor accumulates ab- sentin in the melanoma cytoplasm, 2 AIM2(AIM2) identifies [17]. AIM2 the double-stranded is an intracellular DNA PRR and that initiates identifies inflammasome double- strandedassembly, DNA. leading When to the the DNA activation of replicating of caspase-1, pathogens to the production(e.g., viruses of and IL-1 bacteria) family cytokines, accu- mulatesand/or in tothe cell cytoplasm, death [18 ].AIM2 Although identifies AIM2 the is double-stranded primarily responsible DNA for and the initiates recognition inflam- of ex- masomeogenous assembly, DNA originating leading to from the activation pathogens, of it caspase-1, can detect to mitochondrial the production DNA of (mtDNA)IL-1 family [18 ]. cytokines,Another and/or class to cell of death PRRs important[18]. Although for the AIM2 regulation is primarily of inflammasomes responsible for is the the recog- Toll-like nitionreceptors of exogenous (TLRs) [DNA19,20 ].originating TLRs are type-Ifrom pa integralthogens, membrane it can detect receptors mitochondrial [21]. Their DNA extra- (mtDNA)cellular [18]. domain has several LRRs [21]. When an agonist binds, the extracellular domains ofAnother two TLRs class get of closer, PRRs formingimportant homo- for the or regulation hetero-dimers of inflammasomes and leading tois the an interactionToll-like receptorswith their (TLRs) intracellular [19,20]. TLRs C-terminal are
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