NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
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Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet. 29, 301–305 (2001).
Aganna, E. et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 46, 2445–2452 (2002).
Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348 (2002). References 1–3 report that NLRP3 gain-of-function mutations promote human autoinflammatory diseases.
Mangan, M. S. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17, 588 (2018).
Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426 (2002). This is the first report describing an inflammasome complex that mediates cleavage of IL-1β.
Agostini, L. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004). This is the first report showing that NLRP3 assembles an inflammasome complex that mediates cleavage of IL-1β by caspase 1.
Duncan, J. A. et al. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl Acad. Sci. USA 104, 8041–8046 (2007). This study shows that ATP binding is essential for NLRP3 function, suggesting a therapeutic target for treating NLRP3-related diseases.
Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).
Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156, 1193–1206 (2014). References 9 and 10 show that the PYDs from inflammasome sensors nucleate the polymerization of ASC.
Schmidt, F. I. et al. A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J. Exp. Med. 213, 771–790 (2016).
Boucher, D. et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J. Exp. Med. 215, 827–840 (2018).
Schmid-Burgk, J. L. et al. A genome-wide CRISPR screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J. Biol. Chem. 291, 103–109 (2015).
He, Y., Zeng, M. Y., Yang, D., Motro, B. & Núñez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016).
Shi, H. et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258 (2016). References 13–15 identify NEK7 as an integral component of the NLRP3 inflammasome.
Bauernfeind, F. G. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).
Franchi, L., Eigenbrod, T. & Núñez, G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J. Immunol. 183, 792–796 (2009).
Xing, Y. et al. Cutting edge: TRAF6 mediates TLR/IL-1R signaling-induced nontranscriptional priming of the NLRP3 inflammasome. J. Immunol. 199, 1561–1566 (2017).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).
Perregaux, D. & Gabel, C. A. Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem. 269, 15195–15203 (1994).
Walev, I., Reske, K., Palmer, M., Valeva, A. & Bhakdi, S. Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J. 14, 1607–1614 (1995).
Surprenant, A., Rassendren, F., Kawashima, E., North, R. A. & Buell, G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272, 735–738 (1996).
Samways, D. S., Li, Z. & Egan, T. M. Principles and properties of ion flow in P2X receptors. Front. Cell Neurosci. 8, 6 (2014).
Di, A. et al. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity 49, 56–65 (2018).
Triantafilou, K., Hughes, T. R., Triantafilou, M. & Morgan, B. P. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J. Cell Sci. 126, 2903–2913 (2013).
Laudisi, F. et al. Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release. J. Immunol. 191, 1006–1010 (2013).
Asgari, E. et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122, 3473–3481 (2013).
Muñoz-Planillo, R. et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).
Pétrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).
Gaidt, M. M. et al. Human monocytes engage an alternative inflammasome pathway. Immunity 44, 833–846 (2016).
Groß, C. J. et al. K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity 45, 761–773 (2016).
Wolf, A. J. et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166, 624–636 (2016).
Murakami, T. et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl Acad. Sci. USA 109, 11282–11287 (2012).
Lee, G. S. et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123–127 (2012).
Yaron, J. R. et al. K+ regulates Ca2+ to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis. 6, e1954 (2015).
Katsnelson, M. A., Rucker, L. G., Russo, H. M. & Dubyak, G. R. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J. Immunol. 194, 3937–3952 (2015).
Domingo-Fernández, R., Coll, R. C., Kearney, J., Breit, S. & O’Neill, L. A. J. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. J. Biol. Chem. 292, 12077–12087 (2017).
Tang, T. et al. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat. Commun. 8, 202 (2017).
Green, J. P. et al. Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc. Natl Acad. Sci. USA 115, E9371–E9380 (2018).
Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).
Orlowski, G. M. et al. Multiple cathepsins promote pro-IL-1β synthesis and NLRP3-mediated IL-1β activation. J. Immunol. 195, 1685–1697 (2015).
Katsnelson, M. A., Lozada-Soto, K. M., Russo, H. M., Miller, B. A. & Dubyak, G. R. NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx. Am. J. Physiol. Cell Physiol. 311, C83–C100 (2016).
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).
Cruz, C. M. et al. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem. 282, 2871–2879 (2007).
Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).
Courbet, A. et al. Imidazoquinoxaline anticancer derivatives and imiquimod interact with tubulin: Characterization of molecular microtubule inhibiting mechanisms in correlation with cytotoxicity. PLOS ONE 12, e0182022 (2017).
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).
Bauernfeind, F. et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J. Immunol. 187, 613–617 (2011).
Liu, X. et al. Nuclear factor E2-related factor-2 negatively regulates NLRP3 inflammasome activity by inhibiting reactive oxygen species-induced NLRP3 priming. Antioxid. Redox Signal. 26, 28–43 (2017).
Li, W. et al. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem. Pharmacol. 76, 1485–1489 (2008).
Sussan, T. E. et al. Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. PLOS ONE 3, e3791 (2008).
Freigang, S. et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur. J. Immunol. 41, 2040–2051 (2011).
Zhao, C., Gillette, D. D., Li, X., Zhang, Z. & Wen, H. Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation. J. Biol. Chem. 289, 17020–17029 (2014).
Sogawa, Y. et al. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice. Sci. Rep. 7, 8801 (2017).
Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).
Zhong, Z. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018).
Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
Lemasters, J. J., Theruvath, T. P., Zhong, Z. & Nieminen, A. L. Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta 1787, 1395–1401 (2009).
Man, S. M. et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat. Immunol. 16, 467–475 (2015).
Kuriakose, T., Zheng, M., Neale, G. & Kanneganti, T. D. IRF1 is a transcriptional regulator of ZBP1 promoting NLRP3 inflammasome activation and cell death during influenza virus infection. J. Immunol. 200, 1489–1495 (2018).
Allam, R. et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 15, 982–990 (2014).
Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z. & Germain, R. N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348–361 (2013).
Dudek, J. Role of cardiolipin in mitochondrial signaling pathways. Front. Cell Dev. Biol. 5, 90 (2017).
Iyer, S. S. et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39, 311–323 (2013).
Elliott, E. I. et al. Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming. J. Immunol. 200, 3047–3052 (2018).
Franchi, L. et al. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J. Immunol. 193, 4214–4222 (2014).
Park, S. et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J. Immunol. 191, 4358–4366 (2013).
Ichinohe, T., Yamazaki, T., Koshiba, T. & Yanagi, Y. Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proc. Natl Acad. Sci. USA 110, 17963–17968 (2013).
Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).
Sanman, L. E. et al. Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. eLife 5, e13663 (2016).
Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).
Moon, J. S. et al. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J. Clin. Invest. 125, 665–680 (2015).
Moon, J. S. et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat. Med. 22, 1002–1012 (2016).
Li, X. N. et al. Activation of the AMPK-FOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin. Diabetes 58, 2246–2257 (2009).
Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015). This study shows that an endogenous molecule produced during fasting potently inhibits NLRP3 activation.
Truax, A. D. et al. The inhibitory innate immune sensor NLRP12 maintains a threshold against obesity by regulating gut microbiota homeostasis. Cell Host Microbe 24, 364–378 (2018).
Hughes, M. M. & O’Neill, L. A. J. Metabolic regulation of NLRP3. Immunol. Rev. 281, 88–98 (2018).
Chen, J. & Chen, Z. J. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature 564, 71–76 (2018). This study shows that disassembly of the trans -Golgi network serves as a scaffold for NLRP3 aggregation and activation.
Guo, C. et al. Cholesterol homeostatic regulator SCAP-SREBP2 integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling in macrophages. Immunity 49, 842–856 (2018).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660 (2015).
He, W.-t et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 25, 1285 (2015).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111 (2016).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153 (2016).
Evavold, C. L. et al. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48, 35–44 (2018).
Monteleone, M. et al. Interleukin-1β maturation triggers its relocation to the plasma membrane for gasdermin-D-dependent and -independent secretion. Cell Rep. 24, 1425–1433 (2018).
Groß, O. et al. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36, 388–400 (2012).
Antonopoulos, C. et al. Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J. Biol. Chem. 290, 20167–20184 (2015).
Antonopoulos, C., El Sanadi, C., Kaiser, W. J., Mocarski, E. S. & Dubyak, G. R. Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1β via caspase-8 in dendritic cells. J. Immunol. 191, 4789–4803 (2013).
Bossaller, L. et al. Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner. J. Immunol. 189, 5508–5512 (2012).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011). This study identifies non-canonical NLRP3 activation via LPS-mediated caspase 11 activation and shows it is an important immune mediator during sepsis.
Aachoui, Y. et al. Caspase-11 protects against bacteria that escape the vacuole. Science 339, 975–978 (2013).
Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014). This study shows that caspases 4, 5 and 11 are intracellular receptors for LPS, activation of which induces non-canonical inflammasome activation.
Napier, B. A. et al. Complement pathway amplifies caspase-11-dependent cell death and endotoxin-induced sepsis severity. J. Exp. Med. 213, 2365–2382 (2016).
Man, S. M. et al. IRGB10 liberates bacterial ligands for sensing by the AIM2 and caspase-11-NLRP3 inflammasomes. Cell 167, 382–396 (2016).
Meunier, E. et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509, 366 (2014).
Lee, B. L. et al. Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation. J. Exp. Med. 215, 2279–2288 (2018).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015). Together with references 80 and 81 , this paper shows that cleavage of GSDMD by caspase 1, 4, 5 or 11 during inflammasome activation causes pyroptosis.
Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).
Kerur, N. et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat. Med. 24, 50–61 (2018).
Chu, L. H. et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat. Commun. 9, 996 (2018).
Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D–dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).
Kahlenberg, J. M., Carmona-Rivera, C., Smith, C. K. & Kaplan, M. J. Neutrophil extracellular trap–associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J. Immunol. 190, 1217–1226 (2012).
Netea, M. G. et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood 113, 2324–2335 (2009).
Piccini, A. et al. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way. Proc. Natl Acad. Sci. USA 105, 8067–8072 (2008).
He, Y., Franchi, L. & Núñez, G. TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J. Immunol. 190, 334–339 (2013).
Lin, K.-M. et al. IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc. Natl Acad. Sci. USA 111, 775–780 (2014).
Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010).
Kalantari, P. et al. Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria. Cell Rep. 6, 196–210 (2014).
Karki, R. et al. Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection. Cell Host Microbe 17, 357–368 (2015).
Freeman, L. et al. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med. 214, 1351–1370 (2017).
Swanson, K. V. et al. A noncanonical function of cGAMP in inflammasome priming and activation. J. Exp. Med. 214, 3611–3626 (2017).
Man, S. M. et al. Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex. Proc. Natl Acad. Sci. USA 111, 7403–7408 (2014).
Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395–402 (2010).
Gaidt, M. M. et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171, 1110–1124 (2017).
Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).
Juliana, C. et al. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem. 287, 36617–36622 (2012).
Han, S. et al. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase. J. Biol. Chem. 290, 18124–18133 (2015).
Song, H. et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat. Commun. 7, 13727 (2016).
Yan, Y. et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 62–73 (2015).
Py, B. F., Kim, M.-S., Vakifahmetoglu-Norberg, H. & Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 49, 331–338 (2013).
Rodgers, M. A. et al. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J. Exp. Med. 211, 1333–1347 (2014).
Song, N. et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation. Mol. Cell 68, 185–197 (2017).
Zhang, Z. et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J. Exp. Med. 214, 2671–2693 (2017).
Stutz, A. et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J. Exp. Med. 214, 1725–1736 (2017).
Spalinger, M. R. et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J. Clin. Invest. 126, 1783–1800 (2016).
Mortimer, L., Moreau, F., MacDonald, J. A. & Chadee, K. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat. Immunol. 17, 1176 (2016).
Guo, C. et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45, 802–816 (2016).
Barry, R. et al. SUMO-mediated regulation of NLRP3 modulates inflammasome activity. Nat. Commun. 9, 3001 (2018).
Indramohan, M., Stehlik, C. & Dorfleutner, A. COPs and POPs patrol inflammasome activation. J. Mol. Biol. 430, 153–173 (2018).
Bedoya, F., Sandler, L. L. & Harton, J. A. Pyrin-only protein 2 modulates NF-kappaB and disrupts ASC:CLR interactions. J. Immunol. 178, 3837–3845 (2007).
Ratsimandresy, R. A. et al. The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. Nat. Commun. 8, 15556 (2017).
Periasamy, S. et al. Pyrin-only protein 2 limits inflammation but improves protection against bacteria. Nat. Commun. 8, 15564 (2017).
de Almeida, L. et al. The PYRIN domain-only protein POP1 inhibits inflammasome assembly and ameliorates inflammatory disease. Immunity 43, 264–276 (2015).
Dinarello, C. A., Simon, A. & Van Der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633 (2012).
Ozaki, E., Campbell, M. & Doyle, S. L. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J. Inflamm. Res. 8, 15 (2015).
Brydges, S. D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887 (2009).
Laliberte, R. E. et al. Glutathione S-transferase omega 1–1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1β posttranslational processing. J. Biol. Chem. 278, 16567–16578 (2003).
Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015). This study shows that the small molecule MCC950 specifically inhibits NLRP3 inflammasome activation and is effective in NLRP3-activated mouse disease models.
Dempsey, C. et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav. Immun. 61, 306–316 (2017).
Ismael, S., Nasoohi, S. & Ishrat, T. MCC950, the selective NLRP3 inflammasome inhibitor protects mice against traumatic brain injury. J. Neurotrauma 35, 1294–1303 (2018).
van der Heijden, T. et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E–deficient mice — brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1457–1461 (2017).
Monnerat, G. et al. Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice. Nat. Commun. 7, 13344 (2016).
Van Hout, G. P. et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur. Heart J. 38, 828–836 (2016).
Zhai, Y. et al. Inhibiting the NLRP3 inflammasome activation with MCC950 ameliorates diabetic encephalopathy in db/db mice. Molecules 23, 522 (2018).
Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).
Perera, A. P. et al. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci. Rep. 8, 8618 (2018).
Jiang, H. et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 214, 3219–3238 (2017).
Cocco, M. et al. Development of an acrylate derivative targeting the NLRP3 inflammasome for the treatment of inflammatory bowel disease. J. Med. Chem. 60, 3656–3671 (2017).
Darakhshan, S. & Pour, A. B. Tranilast: a review of its therapeutic applications. Pharmacol. Res. 91, 15–28 (2015).
Huang, Y. et al. Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. EMBO Mol. Med. 10, e8689 (2018).
Ma, Z., Hu, C. & Zhang, Y. Therapeutic effect of Rabdosia rubescens aqueous extract on chronic pharyngitis and its safety [Chinese]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36, 170–173 (2011).
He, H. et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat. Commun. 9, 2550 (2018).
Baldwin, A. G. et al. Boron-based inhibitors of the NLRP3 inflammasome. Cell Chem. Biol. 24, 1321–1335 (2017).
MacKenzie, S. H., Schipper, J. L. & Clark, A. C. The potential for caspases in drug discovery. Curr. Opin. Drug Discov. Develop. 13, 568–576 (2010).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).
Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).
Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J. Clin. Invest. 123, 236–246 (2013).
Lai, M. et al. The NLRP3-caspase 1 inflammasome negatively regulates autophagy via TLR4-TRIF in prion peptide-infected microglia. Front. Aging Neurosci. 10, 116 (2018).
Niemi, K. et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J. Immunol. 186, 6119–6128 (2011).
Babelova, A. et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J. Biol. Chem. 284, 24035–24048 (2009).
Yamasaki, K. et al. NLRP3/cryopyrin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury. J. Biol. Chem. 284, 12762–12771 (2009).
Baron, L. et al. The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine. Cell Death Dis. 6, e1629 (2015).
Martinon, F., Agostini, L., Meylan, E. & Tschopp, J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr. Biol. 14, 1929–1934 (2004).
Abdul-Sater, A. A. et al. Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep. 14, 900–906 (2013).
Sha, W. et al. Human NLRP3 inflammasome senses multiple types of bacterial RNAs. Proc. Natl Acad. Sci. USA 111, 16059–16064 (2014).
Kailasan Vanaja, S. et al. Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome. Proc. Natl Acad. Sci. USA 111, 7765–7770 (2014).
Schweneker, K. et al. The mycobacterial cord factor adjuvant analogue trehalose-6,6′-dibehenate (TDB) activates the Nlrp3 inflammasome. Immunobiology 218, 664–673 (2013).
Greaney, A. J., Leppla, S. H. & Moayeri, M. Bacterial exotoxins and the inflammasome. Front. Immunol. 6, 570 (2015).
Gurcel, L., Abrami, L., Girardin, S., Tschopp, J. & van der Goot, F. G. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135–1145 (2006).
Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).
Mathur, A. et al. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nat. Microbiol. 4, 362–374 (2019).
Lamkanfi, M., Malireddi, R. K. & Kanneganti, T. D. Fungal zymosan and mannan activate the cryopyrin inflammasome. J. Biol. Chem. 284, 20574–20581 (2009).
Kankkunen, P. et al. (1,3)-beta-glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages. J. Immunol. 184, 6335–6342 (2010).
He, Y. et al. 3, 4-Methylenedioxy-β-nitrostyrene inhibits NLRP3 activation by blocking assembly of the inflammasome. J. Biol. Chem. 289, 1142–1150 (2013).
Marchetti, C. et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl Acad. Sci. USA 115, E1530–E1539 (2018).
Juliana, C. et al. Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. J. Biol. Chem. 285, 9792–9802 (2010).
Shim, D.-W. et al. BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination. Sci. Rep. 7, 15020 (2017).
This Review was supported by the National Center for Advancing Translational Sciences, US National Institutes of Health (NIH), through grant KL2TR002490 awarded to K.V.S. and by the NIH through grants AI029564, CA156330, DK094779, AI109965 and AI067798 awarded to J.P.-Y.T. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Leucine-rich repeat domain
(LRR domain). In Toll-like receptors (TLRs), the LRR domain mediates the detection of microbial components; it may serve a similar role in certain NLRs (NACHT–LRR proteins). The LRR domain of NLRs and TLRs is structurally similar. It consists of leucine-rich amino acid strands forming a peptide loop. The loops occur as tandem repeats that together form a coil or solenoid and contain constant sequences, as well as unique insertions or variable residues for each ligand.
A sensor that combines with the adaptor protein ASC and the protease caspase 1 to form the AIM2 inflammasome. It senses cytosolic double-stranded DNA from bacteria or viruses or from mislocalized self-DNA and contributes to infection defence.
- P2X purinoceptor 7
(P2X7). An ATP-gated cation channel that is expressed by haematopoietic cells and participates in cell proliferation and apoptosis. It belongs to the family of purinoceptors for ATP and is responsible for the ATP-dependent activation of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3).
- Caecal ligation and puncture
An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured, thereby forming a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.
The selective removal of mitochondria by macroautophagy under conditions of nutrient starvation or mitochondrial stress.
- Oxidative stress
Cells continuously produce reactive oxygen species (ROS) such as hydrogen peroxide or superoxide anions. Under physiological conditions, mitochondria are the main source, and cellular antioxidants ensure that the redox equilibrium is maintained. During inflammatory responses (and in cancer), excessive production of ROS leads to a metabolic condition known as oxidative stress, which can lead to apoptosis and necrosis.
A cytoplasmic bulk degradation system in which cytoplasmic cargo is targeted and is typically sequestered in double-membrane vesicles, leading to subsequent fusion with the lysosome. This process is essential for the response to starvation because it facilitates the recycling of cellular components. In addition, autophagy can be targeted to intracellular bacteria to restrict their growth.
- Urate crystal model
A mouse model of crystal-induced peritonitis that activates the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome.
A lytic, inflammatory form of programmed cell death that is triggered by cleavage of gasdermin D by the inflammatory caspase 1, 4, 5 or 11. It is characterized by cytoplasmic swelling, early plasma membrane rupture and nuclear condensation. The cytoplasmic content is released into the extracellular space, and this is thought to augment inflammatory and repair responses.
- Neutrophil extracellular traps
(NETs). Fibrous networks that are released into the extracellular environment by neutrophils. They are composed mainly of DNA but also contain proteins from neutrophil granules. NETs act as a mesh that traps microorganisms and exposes them to neutrophil-derived effector molecules.
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Swanson, K.V., Deng, M. & Ting, J.PY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19, 477–489 (2019). https://doi.org/10.1038/s41577-019-0165-0
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