The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation
<p>A Two-Signal Model for NLRP3 Inflammasome Activation. The priming signal (signal 1, <b>left</b>) is provided by microbial components or endogenous cytokines, leading to the activation of the transcription factor NF-κB and subsequent upregulation of NLRP3 and pro-interleukin-1β (pro-IL-1β). Caspase-8 and FAS-mediated death domain protein (FADD), and NOD1/2 are involved in the priming step by regulating the NF-κB pathway. NLRP3 undergoes post-translational modifications that license its activation. The activation signal (signal 2, <b>right</b>) is provided by a variety of stimuli including extracellular ATP, pore-forming toxins, RNA viruses, and particulate matter. Multiple molecular or cellular events, including ionic flux, mitochondrial dysfunction and reactive oxygen species (ROS) generation, and lysosomal damage, have been shown to activate the NLRP3 inflammasome. BRCC3, BRCA1/BRCA2-containing complex subunit 3; IL-1R, IL-1β receptor; JNK1, JUN N-terminal kinase 1; PKD, protein kinase D; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor.</p> "> Figure 2
<p>Mechanism of Activation for the Non-Canonical and Alternative NLRP3 Inflammasome Pathways. Non-canonical NLRP3 inflammasome activation (<b>left</b>) is induced by LPS internalization into the cytosol by transfection or infection. Caspase-11/4/5 induces pyroptosis through the cleavage of GSDMD. This process also activates pannexin-1 through caspase-11 to release ATP and induce K<sup>+</sup> efflux, which drives NLRP3 inflammasome assembly and release of IL-1β. The alternative NLRP3 inflammasome (<b>right</b>) is activated in human monocytes in response to LPS and requires receptor-interacting serine/threonine-protein kinase 1 (RIPK1), FADD, and caspase-8 for its activation. This pathway is K<sup>+</sup> efflux independent and does not induce pyroptosis.</p> "> Figure 3
<p>Post-translational Modifications and Regulators of NLRP3. NLRP3 is regulated via phosphorylation (P), ubiquitination (Ub), sumolyation (S), and s-nitrosylation (SN) through post-translational modifications. Post-translational modifications that positively affect NLRP3 activation are listed on the left and those that negatively act on NLRP3 to inhibit its activation are listed in the middle. Interacting partners of NLRP3 are listed on the right. ARIH2, ariadne homolog 2; BRCC3, BRCA1/BRCA2-containing complex subunit 3; FBX12, F-box/LRR-repeat protein 2; FBXO3, F-box only protein 3; JNK1, JUN N-terminal kinase 1; MAPL, mitochondrial-anchored protein ligase; MARCH7, membrane-associated RING finger protein 7; NO, nitric oxide; PKA, protein kinase A; PKD, protein kinase D; PP2A, phosphatase 2A; PTPN22, protein tyrosine phosphatase non-receptor 22; SENP6/7, sentrin/SUMO-specific proteases. GBP5, guanylate-binding protein 5; Hsp90, heat-shock protein 90; MARK4, microtubule-affinity regulating kinase 4; MIF, macrophage migration inhibitory factor; NEK7, NIMA-related kinase 7; PKR, double-stranded RNA-dependent protein kinase; STG1, suppressor of the G2 allele of skp1; TXNIP, thioredoxin-interacting protein.</p> ">
Abstract
:1. Introduction
2. Priming the NLRP3 Inflammasome (Signal 1)
3. Activating the NLRP3 Inflammasome (Signal 2)
3.1. Ionic Flux
3.1.1. K+ Efflux
3.1.2. Ca2+ Mobilization
3.1.3. Na+ Influx and Cl− Efflux
3.2. Reactive Oxygen Species (ROS) and Mitochondrial Dysfunction
3.3. Lysosomal Damage
4. Activation of the Non-Canonical Inflammasome Pathway and Alternative Inflammasome Pathway
4.1. The Non-Canonical Inflammasome Pathway
4.2. The Alternative Inflammasome Pathway
5. Regulation of the NLRP3 Inflammasome
5.1. Regulation by Post-Translational Modifications of NLRP3
5.1.1. Ubiquitination
5.1.2. Phosphorylation
5.1.3. Other Post-Translational Modifications
5.2. Regulation by NLRP3 Interacting Partners
6. Concluding Remarks and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
PRR | Pattern-recognition receptor |
PAMP | Pathogen-associated molecular pattern |
DAMP | Damage-associated molecular pattern |
PYD | Pyrin domain |
NOD | Nucleotide-binding oligomerization domain |
LRR | Leucine-rich repeat |
NLR | Nod-like receptor |
NLRP | Nod-like receptor protein |
NLRP3 | NLR family pyrin domain containing 3 |
NLRC4 | NLR family CARD domain-containing protein 4 |
AIM2 | Absent-in-melanoma 2 |
ASC | Apoptosis-associated speck-like protein containing a caspase-recruitment domain |
IL | Interleukin |
IFN | Interferon |
GSDMD | Gasdermin D |
CAPS | Cryopyrin-associated periodic syndromes |
IL-1R | IL-1 receptor |
MCC950 | 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-[4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonylurea |
PtdIns4 | Phosphatidylinositol-4-phosphate |
ATP | Adenosine triphosphate |
TLR | Toll-like receptors |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
MYD88 | Myeloid differentiation primary response 88 |
TRIF | TIR-domain-containing adapter-inducing interferon-β |
FADD | Fas-associated protein with death domain |
LPS | Lipopolysaccharide |
IRAK | IL-1 receptor-associated kinase |
IKK | Inhibitor of NF-κB kinase |
BRCC | BRCA1-BRCA2-containing complex |
JNK | c-Jun N-terminal kinase |
IRF1 | Interferon regulatory transcription factor 1 |
mtDNA | Mitochondrial DNA |
PLC | Phospholipase C |
CL097 | 2-(ethoxymethyl)-3H-imidazo[4,5-c]quinolin-4-amine |
BAPTA-AM | 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) |
NADPH | Nicotinamide adenine dinucleotide phosphate |
GPCR | G protein-coupled receptor |
CaSR | Calcium-sensing receptor |
GPRC6A | G protein-coupled receptor family C group 6 member A |
PIP2 | Phosphatidylinositol 4,5-bisphosphate |
IP3 | Inositol 1,4,5-triphosphate |
ER | Endoplasmic reticulum |
IP3R | IP3 receptor |
2APB | 2-aminoethoxy diphenylborinate |
P2RX7 | P2X purinoceptor 7 |
TRPM | Transient receptor potential ion melastatin |
TRPV | Transient receptor potential ion vanilloid |
TXNIP | Thioredoxin interacting protein |
MSU | Monosodium urate |
VRAC | Volume-related anion channel |
CLIC | Chloride intracellular channel |
ROS | Reactive oxygen species |
NOX2 | NADPH oxidase 2 |
NOX4 | NADPH oxidase 4 |
CPT1A | Carnitine palmitoyltransferase 1A |
mtROS | Mitochondrial ROS |
MAVS | Mitochondrial antiviral-signaling protein |
TRAF3 | TNF receptor associated factor 3 |
oxPAPC | Oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine |
GBP2 | Guanylate-binding protein 2 |
IRGB10 | Immunity-related GTPase family member b10 |
RIPK1 | Receptor-interacting serine/threonine-protein kinase 1 |
CASP8 | Caspase-8 |
DUB | Deubiquitinating enzyme |
SCF | Skp-Cullin-F box |
FBXL2 | F-box L2 |
FBXO3 | F-box O3 |
MARCH7 | Membrane-associated RING-CH protein VII |
DRD1 | Dopamine D1 receptor |
TRIM31 | Tripartite Motif Containing 31 |
ARIH2 | Ariadne homolog 2 |
USP | Ubiquitin specific peptidase |
PKA | Protein kinase A |
cAMP | Cyclic AMP |
MAM | Mitochondria-associated membrane |
DAG | Diacylglycerol |
PTPN22 | Protein tyrosine phosphatase, non-receptor type 22 |
PP2A | Phosphotase 2A |
MAPL | Mitochondrial-anchored protein ligase |
SENP | Sentrin/SUMO-specific protease |
HSP90 | Heat shock protein 90 |
SGT1 | Suppressor of G2 allele of SKP1 |
TXNIP | Thioredoxin-interacting protein |
GBP5 | Guanylate-binding protein 5 |
PKR | Double-stranded RNA-dependent protein kinase |
MIF | Migration inhibitory factor |
MARK4 | Microtubule-affinity regulating kinase 4 |
Nek7 | NIMA-related kinase 7 |
References
- Takeuchi, O.; Akira, S. Pattern recognition receptors and inflammation. Cell 2010, 140, 805–820. [Google Scholar] [CrossRef] [PubMed]
- Franchi, L.; Eigenbrod, T.; Muñoz-Planillo, R.; Nuñez, G. The Inflammasome: A Caspase-1 Activation Platform Regulating Immune Responses and Disease Pathogenesis. Nat. Immunol. 2009, 10, 241. [Google Scholar] [CrossRef] [PubMed]
- Sharma, D.; Kanneganti, T.-D. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J. Cell Biol. 2016, 213, 617–629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lamkanfi, M.; Dixit, V.M. Mechanisms and Functions of Inflammasomes. Cell 2014, 157, 1013–1022. [Google Scholar] [CrossRef] [PubMed]
- Elinav, E.; Strowig, T.; Kau, A.L.; Henao-Mejia, J.; Thaiss, C.A.; Booth, C.J.; Peaper, D.R.; Bertin, J.; Eisenbarth, S.C.; Gordon, J.I.; et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 2011, 145, 745–757. [Google Scholar] [CrossRef] [PubMed]
- Kerur, N.; Veettil, M.V.; Sharma-Walia, N.; Bottero, V.; Sadagopan, S.; Otageri, P.; Chandran, B. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 2011, 9, 363–375. [Google Scholar] [CrossRef] [PubMed]
- Khare, S.; Dorfleutner, A.; Bryan, N.B.; Yun, C.; Radian, A.D.; de Almeida, L.; Rojanasakul, Y.; Stehlik, C. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 2012, 36, 464–476. [Google Scholar] [CrossRef]
- Minkiewicz, J.; de Rivero Vaccari, J.P.; Keane, R.W. Human astrocytes express a novel NLRP2 inflammasome. Glia 2013, 61, 1113–1121. [Google Scholar] [CrossRef]
- Vladimer, G.I.; Weng, D.; Paquette, S.W.M.; Vanaja, S.K.; Rathinam, V.A.K.; Aune, M.H.; Conlon, J.E.; Burbage, J.J.; Proulx, M.K.; Liu, Q.; et al. The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 2012, 37, 96–107. [Google Scholar] [CrossRef]
- Fernandes-Alnemri, T.; Wu, J.; Yu, J.-W.; Datta, P.; Miller, B.; Jankowski, W.; Rosenberg, S.; Zhang, J.; Alnemri, E.S. The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007, 14, 1590–1604. [Google Scholar] [CrossRef]
- Manji, G.A.; Wang, L.; Geddes, B.J.; Brown, M.; Merriam, S.; Al-Garawi, A.; Mak, S.; Lora, J.M.; Briskin, M.; Jurman, M.; et al. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B. J. Biol. Chem. 2002, 277, 11570–11575. [Google Scholar] [CrossRef] [PubMed]
- Franchi, L.; Warner, N.; Viani, K.; Nuñez, G. Function of Nod-like receptors in microbial recognition and host defense. Immunol. Rev. 2009, 227, 106–128. [Google Scholar] [CrossRef] [PubMed]
- Martinon, F.; Burns, K.; Tschopp, J. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-β. Mol. Cell 2002, 10, 417–426. [Google Scholar] [CrossRef]
- Dinarello, C.A. Immunological and Inflammatory Functions of the Interleukin-1 Family. Annu. Rev. Immunol. 2009, 27, 519–550. [Google Scholar] [CrossRef] [PubMed]
- Fink, S.L.; Cookson, B.T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell. Microbiol. 2006, 8, 1812–1825. [Google Scholar] [CrossRef] [PubMed]
- Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015, 526, 660–665. [Google Scholar] [CrossRef] [PubMed]
- Kayagaki, N.; Stowe, I.B.; Lee, B.L.; O’Rourke, K.; Anderson, K.; Warming, S.; Cuellar, T.; Haley, B.; Roose-Girma, M.; Phung, Q.T.; et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015, 526, 666–671. [Google Scholar] [CrossRef]
- He, W.; Wan, H.; Hu, L.; Chen, P.; Wang, X.; Huang, Z.; Yang, Z.-H.; Zhong, C.-Q.; Han, J. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015, 25, 1285–1298. [Google Scholar] [CrossRef]
- Miao, E.A.; Leaf, I.A.; Treuting, P.M.; Mao, D.P.; Dors, M.; Sarkar, A.; Warren, S.E.; Wewers, M.D.; Aderem, A. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 2010, 11, 1136–1142. [Google Scholar] [CrossRef]
- Thomas, P.G.; Dash, P.; Aldridge, J.R.; Ellebedy, A.H.; Reynolds, C.; Funk, A.J.; Martin, W.J.; Lamkanfi, M.; Webby, R.J.; Boyd, K.L.; et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 2009, 30, 566–575. [Google Scholar] [CrossRef]
- Allen, I.C.; Scull, M.A.; Moore, C.B.; Holl, E.K.; McElvania-TeKippe, E.; Taxman, D.J.; Guthrie, E.H.; Pickles, R.J.; Ting, J.P.-Y. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 2009, 30, 556–565. [Google Scholar] [CrossRef] [PubMed]
- Gross, O.; Poeck, H.; Bscheider, M.; Dostert, C.; Hannesschläger, N.; Endres, S.; Hartmann, G.; Tardivel, A.; Schweighoffer, E.; Tybulewicz, V.; et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 2009, 459, 433–436. [Google Scholar] [CrossRef] [PubMed]
- Kanneganti, T.-D.; Body-Malapel, M.; Amer, A.; Park, J.-H.; Whitfield, J.; Franchi, L.; Taraporewala, Z.F.; Miller, D.; Patton, J.T.; Inohara, N.; et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 2006, 281, 36560–36568. [Google Scholar] [CrossRef] [PubMed]
- Menu, P.; Vince, J.E. The NLRP3 inflammasome in health and disease: The good, the bad and the ugly. Clin. Exp. Immunol. 2011, 166, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Guo, H.; Callaway, J.B.; Ting, J.P.-Y. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 2015, 21, 677–687. [Google Scholar] [CrossRef] [PubMed]
- Vajjhala, P.R.; Mirams, R.E.; Hill, J.M. Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J. Biol. Chem. 2012, 287, 41732–41743. [Google Scholar] [CrossRef] [PubMed]
- Duncan, J.A.; Bergstralh, D.T.; Wang, Y.; Willingham, S.B.; Ye, Z.; Zimmermann, A.G.; Ting, J.P.-Y. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl. Acad. Sci. USA 2007, 104, 8041–8046. [Google Scholar] [CrossRef] [Green Version]
- Coll, R.C.; Hill, J.R.; Day, C.J.; Zamoshnikova, A.; Boucher, D.; Massey, N.L.; Chitty, J.L.; Fraser, J.A.; Jennings, M.P.; Robertson, A.A.B.; et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 2019, 15, 556. [Google Scholar] [CrossRef]
- Coll, R.C.; Robertson, A.A.B.; Chae, J.J.; Higgins, S.C.; Muñoz-Planillo, R.; Inserra, M.C.; Vetter, I.; Dungan, L.S.; Monks, B.G.; Stutz, A.; et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015, 21, 248–255. [Google Scholar] [CrossRef] [Green Version]
- Tapia-Abellán, A.; Angosto-Bazarra, D.; Martínez-Banaclocha, H.; Torre-Minguela, C.d.; Cerón-Carrasco, J.P.; Pérez-Sánchez, H.; Arostegui, J.I.; Pelegrin, P. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat. Chem. Biol. 2019, 15, 560. [Google Scholar] [CrossRef]
- Hafner-Bratkovič, I.; Sušjan, P.; Lainšček, D.; Tapia-Abellán, A.; Cerović, K.; Kadunc, L.; Angosto-Bazarra, D.; Pelegrίn, P.; Jerala, R. NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat. Commun. 2018, 9, 5182. [Google Scholar] [CrossRef] [PubMed]
- Lamkanfi, M.; Kanneganti, T.-D. Nlrp3: An immune sensor of cellular stress and infection. Int. J. Biochem. Cell Biol. 2010, 42, 792–795. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B.G.; Fitzgerald, K.A.; et al. Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression. J. Immunol. 2009, 183, 787–791. [Google Scholar] [CrossRef] [PubMed]
- Franchi, L.; Eigenbrod, T.; Núñez, G. Cutting Edge: TNF-α Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation. J. Immunol. 2009, 183, 792–796. [Google Scholar] [CrossRef] [PubMed]
- Gurung, P.; Anand, P.K.; Malireddi, R.K.S.; Walle, L.V.; Opdenbosch, N.V.; Dillon, C.P.; Weinlich, R.; Green, D.R.; Lamkanfi, M.; Kanneganti, T.-D. FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes. J. Immunol. 2014, 192, 1835–1846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Allam, R.; Lawlor, K.E.; Yu, E.C.-W.; Mildenhall, A.L.; Moujalled, D.M.; Lewis, R.S.; Ke, F.; Mason, K.D.; White, M.J.; Stacey, K.J.; et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 2014, 15, 982–990. [Google Scholar] [CrossRef]
- Lemmers, B.; Salmena, L.; Bidère, N.; Su, H.; Matysiak-Zablocki, E.; Murakami, K.; Ohashi, P.S.; Jurisicova, A.; Lenardo, M.; Hakem, R.; et al. Essential Role for Caspase-8 in Toll-like Receptors and NFκB Signaling. J. Biol. Chem. 2007, 282, 7416–7423. [Google Scholar] [CrossRef]
- Ranjan, K.; Pathak, C. FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis. Sci. Rep. 2016, 6, 22787. [Google Scholar] [CrossRef]
- Juliana, C.; Fernandes-Alnemri, T.; Kang, S.; Farias, A.; Qin, F.; Alnemri, E.S. Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation. J. Biol. Chem. 2012, 287, 36617–36622. [Google Scholar] [CrossRef] [Green Version]
- Schroder, K.; Sagulenko, V.; Zamoshnikova, A.; Richards, A.A.; Cridland, J.A.; Irvine, K.M.; Stacey, K.J.; Sweet, M.J. Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction. Immunobiology 2012, 217, 1325–1329. [Google Scholar] [CrossRef] [Green Version]
- Lin, K.-M.; Hu, W.; Troutman, T.D.; Jennings, M.; Brewer, T.; Li, X.; Nanda, S.; Cohen, P.; Thomas, J.A.; Pasare, C. IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc. Natl. Acad. Sci. USA 2014, 111, 775–780. [Google Scholar] [CrossRef] [PubMed]
- Fernandes-Alnemri, T.; Kang, S.; Anderson, C.; Sagara, J.; Fitzgerald, K.A.; Alnemri, E.S. Toll-Like Receptor Signaling Licenses IRAK1 For Rapid Activation Of The NLRP3 Inflammasome. J. Immunol. Baltim. Md 1950 2013, 191, 3995–3999. [Google Scholar]
- Kim, S.-J.; Cha, J.-Y.; Kang, H.S.; Lee, J.-H.; Lee, J.Y.; Park, J.-H.; Bae, J.-H.; Song, D.-K.; Im, S.-S. Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages. BMB Rep. 2016, 49, 276–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lopez-Castejon, G.; Luheshi, N.M.; Compan, V.; High, S.; Whitehead, R.C.; Flitsch, S.; Kirov, A.; Prudovsky, I.; Swanton, E.; Brough, D. Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome. J. Biol. Chem. 2013, 288, 2721–2733. [Google Scholar] [CrossRef] [PubMed]
- Py, B.F.; Kim, M.-S.; Vakifahmetoglu-Norberg, H.; Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 2013, 49, 331–338. [Google Scholar] [CrossRef] [PubMed]
- Song, N.; Liu, Z.-S.; Xue, W.; Bai, Z.-F.; Wang, Q.-Y.; Dai, J.; Liu, X.; Huang, Y.-J.; Cai, H.; Zhan, X.-Y.; et al. NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation. Mol. Cell 2017, 68, 185–197.e6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhong, Z.; Liang, S.; Sanchez-Lopez, E.; He, F.; Shalapour, S.; Lin, X.; Wong, J.; Ding, S.; Seki, E.; Schnabl, B.; et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 2018, 560, 198–203. [Google Scholar] [CrossRef] [PubMed]
- Mariathasan, S.; Weiss, D.S.; Newton, K.; McBride, J.; O’Rourke, K.; Roose-Girma, M.; Lee, W.P.; Weinrauch, Y.; Monack, D.M.; Dixit, V.M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006, 440, 228–232. [Google Scholar] [CrossRef]
- Silveira, A.A.; Cunningham, C.; Corr, E.; Ferreira, W.A.; Costa, F.F.; Almeida, C.B.; Conran, N.; Dunne, A. Heme Induces NLRP3 Inflammasome Formation in Primary Human Macrophages and May Propagate Hemolytic Inflammatory Processes By Inducing S100A8 Expression. Blood 2016, 128, 1256. [Google Scholar]
- Erdei, J.; Tóth, A.; Balogh, E.; Nyakundi, B.B.; Bányai, E.; Ryffel, B.; Paragh, G.; Cordero, M.D.; Jeney, V. Induction of NLRP3 Inflammasome Activation by Heme in Human Endothelial Cells. Oxid. Med. Cell. Longev. 2018, 2018, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Martinon, F.; Pétrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440, 237–241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hornung, V.; Bauernfeind, F.; Halle, A.; Samstad, E.O.; Kono, H.; Rock, K.L.; Fitzgerald, K.A.; Latz, E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 2008, 9, 847–856. [Google Scholar] [CrossRef] [PubMed]
- Dostert, C.; Pétrilli, V.; Bruggen, R.V.; Steele, C.; Mossman, B.T.; Tschopp, J. Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica. Science 2008, 320, 674–677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eigenbrod, T.; Dalpke, A.H. Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses. J. Immunol. 2015, 195, 411–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, R.; Ghosh, S.; Monks, B.; DeOliveira, R.B.; Tzeng, T.-C.; Kalantari, P.; Nandy, A.; Bhattacharjee, B.; Chan, J.; Ferreira, F.; et al. RNA and β-hemolysin of group B Streptococcus induce interleukin-1β (IL-1β) by activating NLRP3 inflammasomes in mouse macrophages. J. Biol. Chem. 2014, 289, 13701–13705. [Google Scholar] [CrossRef] [PubMed]
- Kanneganti, T.-D.; Ozören, N.; Body-Malapel, M.; Amer, A.; Park, J.-H.; Franchi, L.; Whitfield, J.; Barchet, W.; Colonna, M.; Vandenabeele, P.; et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006, 440, 233–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sha, W.; Mitoma, H.; Hanabuchi, S.; Bao, M.; Weng, L.; Sugimoto, N.; Liu, Y.; Zhang, Z.; Zhong, J.; Sun, B.; et al. Human NLRP3 inflammasome senses multiple types of bacterial RNAs. Proc. Natl. Acad. Sci. USA 2014, 111, 16059–16064. [Google Scholar] [CrossRef] [Green Version]
- Greaney, A.J.; Leppla, S.H.; Moayeri, M. Bacterial Exotoxins and the Inflammasome. Front. Immunol. 2015, 6, 570. [Google Scholar] [CrossRef]
- Lee, M.-S.; Kwon, H.; Lee, E.-Y.; Kim, D.-J.; Park, J.-H.; Tesh, V.L.; Oh, T.-K.; Kim, M.H. Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1β and Apoptotic Cell Death. Infect. Immun. 2016, 84, 172–186. [Google Scholar] [CrossRef]
- Kasper, L.; König, A.; Koenig, P.-A.; Gresnigt, M.S.; Westman, J.; Drummond, R.A.; Lionakis, M.S.; Groß, O.; Ruland, J.; Naglik, J.R.; et al. The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat. Commun. 2018, 9, 4260. [Google Scholar] [CrossRef]
- Rogiers, O.; Frising, U.C.; Kucharíková, S.; Jabra-Rizk, M.A.; Loo, G.v.; Dijck, P.V.; Wullaert, A. Candidalysin Crucially Contributes to Nlrp3 Inflammasome Activation by Candida albicans Hyphae. mBio 2019, 10, e02221-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Skeldon, A.; Saleh, M. The Inflammasomes: Molecular Effectors of Host Resistance Against Bacterial, Viral, Parasitic, and Fungal Infections. Front. Microbiol. 2011, 2, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mathur, A.; Feng, S.; Hayward, J.A.; Ngo, C.; Fox, D.; Atmosukarto, I.I.; Price, J.D.; Schauer, K.; Märtlbauer, E.; Robertson, A.A.B.; et al. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nat. Microbiol. 2019, 4, 362. [Google Scholar] [CrossRef] [PubMed]
- 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. 1994, 269, 15195–15203. [Google Scholar] [PubMed]
- Walev, I.; Klein, J.; Husmann, M.; Valeva, A.; Strauch, S.; Wirtz, H.; Weichel, O.; Bhakdi, S. Potassium Regulates IL-1β Processing Via Calcium-Independent Phospholipase A2. J. Immunol. 2000, 164, 5120–5124. [Google Scholar] [CrossRef]
- Walev, I.; Reske, K.; Palmer, M.; Valeva, A.; Bhakdi, S. Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J. 1995, 14, 1607–1614. [Google Scholar] [CrossRef] [PubMed]
- Muñoz-Planillo, R.; Kuffa, P.; Martínez-Colón, G.; Smith, B.L.; Rajendiran, T.M.; Núñez, G. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 2013, 38, 1142–1153. [Google Scholar] [CrossRef] [PubMed]
- Pétrilli, V.; Papin, S.; Dostert, C.; Mayor, A.; Martinon, F.; Tschopp, J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007, 14, 1583–1589. [Google Scholar] [CrossRef]
- Rühl, S.; Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur. J. Immunol. 2015, 45, 2927–2936. [Google Scholar] [CrossRef]
- Schmid-Burgk, J.L.; Gaidt, M.M.; Schmidt, T.; Ebert, T.S.; Bartok, E.; Hornung, V. Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur. J. Immunol. 2015, 45, 2911–2917. [Google Scholar] [CrossRef]
- Yang, D.; He, Y.; Muñoz-Planillo, R.; Liu, Q.; Núñez, G. Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock. Immunity 2015, 43, 923–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Groß, C.J.; Mishra, R.; Schneider, K.S.; Médard, G.; Wettmarshausen, J.; Dittlein, D.C.; Shi, H.; Gorka, O.; Koenig, P.-A.; Fromm, S.; et al. K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. Immunity 2016, 45, 761–773. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sanman, L.E.; Qian, Y.; Eisele, N.A.; Ng, T.M.; van der Linden, W.A.; Monack, D.M.; Weerapana, E.; Bogyo, M. Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. eLife 2016, 5, e13663. [Google Scholar] [CrossRef] [PubMed]
- Meng, G.; Zhang, F.; Fuss, I.; Kitani, A.; Strober, W. A Mutation in the Nlrp3 Gene Causing Inflammasome Hyperactivation Potentiates Th17 Cell-Dominant Immune Responses. Immunity 2009, 30, 860–874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clapham, D.E. Calcium signaling. Cell 2007, 131, 1047–1058. [Google Scholar] [CrossRef] [PubMed]
- Brough, D.; Feuvre, R.A.L.; Wheeler, R.D.; Solovyova, N.; Hilfiker, S.; Rothwell, N.J.; Verkhratsky, A. Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages. J. Immunol. 2003, 170, 3029–3036. [Google Scholar] [CrossRef] [PubMed]
- Feldmeyer, L.; Keller, M.; Niklaus, G.; Hohl, D.; Werner, S.; Beer, H.-D. The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr. Biol. CB 2007, 17, 1140–1145. [Google Scholar] [CrossRef] [PubMed]
- Chu, J.; Thomas, L.M.; Watkins, S.C.; Franchi, L.; Núñez, G.; Salter, R.D. Cholesterol-dependent cytolysins induce rapid release of mature IL-1β from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J. Leukoc. Biol. 2009, 86, 1227–1238. [Google Scholar] [CrossRef]
- Murakami, T.; Ockinger, J.; Yu, J.; Byles, V.; McColl, A.; Hofer, A.M.; Horng, T. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl. Acad. Sci. USA 2012, 109, 11282–11287. [Google Scholar] [CrossRef] [Green Version]
- Lee, G.-S.; Subramanian, N.; Kim, A.I.; Aksentijevich, I.; Goldbach-Mansky, R.; Sacks, D.B.; Germain, R.N.; Kastner, D.L.; Chae, J.J. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 2012, 492, 123–127. [Google Scholar] [CrossRef] [Green Version]
- 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. 2015, 194, 3937–3952. [Google Scholar] [CrossRef] [PubMed]
- Baldwin, A.G.; Rivers-Auty, J.; Daniels, M.J.D.; White, C.S.; Schwalbe, C.H.; Schilling, T.; Hammadi, H.; Jaiyong, P.; Spencer, N.G.; England, H.; et al. Boron-Based Inhibitors of the NLRP3 Inflammasome. Cell Chem. Biol. 2017, 24, 1321–1335.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Compan, V.; Baroja-Mazo, A.; López-Castejón, G.; Gomez, A.I.; Martínez, C.M.; Angosto, D.; Montero, M.T.; Herranz, A.S.; Bazán, E.; Reimers, D.; et al. Cell Volume Regulation Modulates NLRP3 Inflammasome Activation. Immunity 2012, 37, 487–500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhong, Z.; Zhai, Y.; Liang, S.; Mori, Y.; Han, R.; Sutterwala, F.S.; Qiao, L. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 2013, 4, 1611. [Google Scholar] [CrossRef] [PubMed]
- Weber, K.; Schilling, J.D. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J. Biol. Chem. 2014, 289, 9158–9171. [Google Scholar] [CrossRef] [PubMed]
- Schorn, C.; Frey, B.; Lauber, K.; Janko, C.; Strysio, M.; Keppeler, H.; Gaipl, U.S.; Voll, R.E.; Springer, E.; Munoz, L.E.; et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 2011, 286, 35–41. [Google Scholar] [CrossRef] [PubMed]
- Verhoef, P.A.; Kertesy, S.B.; Lundberg, K.; Kahlenberg, J.M.; Dubyak, G.R. Inhibitory effects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J. Immunol. Baltim. Md 1950 2005, 175, 7623–7634. [Google Scholar]
- Perregaux, D.G.; Laliberte, R.E.; Gabel, C.A. Human monocyte interleukin-1beta posttranslational processing. Evidence of a volume-regulated response. J. Biol. Chem. 1996, 271, 29830–29838. [Google Scholar] [CrossRef]
- Tang, T.; Lang, X.; Xu, C.; Wang, X.; Gong, T.; Yang, Y.; Cui, J.; Bai, L.; Wang, J.; Jiang, W.; et al. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat. Commun. 2017, 8, 202. [Google Scholar] [CrossRef]
- Daniels, M.J.D.; Rivers-Auty, J.; Schilling, T.; Spencer, N.G.; Watremez, W.; Fasolino, V.; Booth, S.J.; White, C.S.; Baldwin, A.G.; Freeman, S.; et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat. Commun. 2016, 7, 12504. [Google Scholar] [CrossRef]
- 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. 2017, 292, 12077–12087. [Google Scholar] [CrossRef] [PubMed]
- Green, J.P.; Yu, S.; Martín-Sánchez, F.; Pelegrin, P.; Lopez-Castejon, G.; Lawrence, C.B.; Brough, D. Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc. Natl. Acad. Sci. USA 2018, 115, E9371–E9380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cruz, C.M.; Rinna, A.; Forman, H.J.; Ventura, A.L.M.; Persechini, P.M.; Ojcius, D.M. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem. 2007, 282, 2871–2879. [Google Scholar] [CrossRef] [PubMed]
- van Bruggen, R.; Köker, M.Y.; Jansen, M.; van Houdt, M.; Roos, D.; Kuijpers, T.W.; van den Berg, T.K. Human NLRP3 inflammasome activation is Nox1-4 independent. Blood 2010, 115, 5398–5400. [Google Scholar] [CrossRef] [PubMed]
- Ma, M.W.; Wang, J.; Dhandapani, K.M.; Brann, D.W. NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury. Oxid. Med. Cell. Longev. 2017, 2017, 6057609. [Google Scholar] [CrossRef] [PubMed]
- Moon, J.-S.; Nakahira, K.; Chung, K.-P.; DeNicola, G.M.; Koo, M.J.; Pabón, M.A.; Rooney, K.T.; Yoon, J.-H.; Ryter, S.W.; Stout-Delgado, H.; et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat. Med. 2016, 22, 1002–1012. [Google Scholar] [CrossRef] [PubMed]
- Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011, 469, 221–225. [Google Scholar] [CrossRef]
- Nakahira, K.; Haspel, J.A.; Rathinam, V.A.K.; Lee, S.-J.; Dolinay, T.; Lam, H.C.; Englert, J.A.; Rabinovitch, M.; Cernadas, M.; Kim, H.P.; et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 2011, 12, 222–230. [Google Scholar] [CrossRef]
- Shimada, K.; Crother, T.R.; Karlin, J.; Dagvadorj, J.; Chiba, N.; Chen, S.; Ramanujan, V.K.; Wolf, A.J.; Vergnes, L.; Ojcius, D.M.; et al. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis. Immunity 2012, 36, 401–414. [Google Scholar] [CrossRef] [Green Version]
- Bauernfeind, F.; Bartok, E.; Rieger, A.; Franchi, L.; Núñez, G.; Hornung, V. Cutting edge: Reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J. Immunol. Baltim. Md 1950 2011, 187, 613–617. [Google Scholar] [CrossRef]
- Park, S.; Juliana, C.; Hong, S.; Datta, P.; Hwang, I.; Fernandes-Alnemri, T.; Yu, J.-W.; Alnemri, E.S. The mitochondrial anti-viral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J. Immunol. Baltim. Md 1950 2013, 191, 4358–4366. [Google Scholar]
- Subramanian, N.; Natarajan, K.; Clatworthy, M.R.; Wang, Z.; Germain, R.N. The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation. Cell 2013, 153, 348–361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ermler, M.E.; Traylor, Z.; Patel, K.; Schattgen, S.A.; Vanaja, S.K.; Fitzgerald, K.A.; Hise, A.G. Rift Valley fever virus infection induces activation of the NLRP3 inflammasome. Virology 2014, 449, 174–180. [Google Scholar] [CrossRef] [PubMed]
- Franchi, L.; Eigenbrod, T.; Muñoz-Planillo, R.; Ozkurede, U.; Kim, Y.-G.; Chakrabarti, A.; Gale, M.; Silverman, R.H.; Colonna, M.; Akira, S.; et al. Cytosolic Double-Stranded RNA Activates the NLRP3 Inflammasome via MAVS-Induced Membrane Permeabilization and K+ Efflux. J. Immunol. 2014, 193, 4214–4222. [Google Scholar] [CrossRef] [PubMed]
- Guan, K.; Wei, C.; Zheng, Z.; Song, T.; Wu, F.; Zhang, Y.; Cao, Y.; Ma, S.; Chen, W.; Xu, Q.; et al. MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked Ubiquitination via the E3 Ligase TRAF3. J. Immunol. 2015, 194, 4880–4890. [Google Scholar] [CrossRef] [PubMed]
- 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 2013, 110, 17963–17968. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Iyer, S.S.; He, Q.; Janczy, J.R.; Elliott, E.I.; Zhong, Z.; Olivier, A.K.; Sadler, J.J.; Knepper-Adrian, V.; Han, R.; Qiao, L.; et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 2013, 39, 311–323. [Google Scholar] [CrossRef] [PubMed]
- Elliott, E.I.; Miller, A.N.; Banoth, B.; Iyer, S.S.; Stotland, A.; Weiss, J.P.; Gottlieb, R.A.; Sutterwala, F.S.; Cassel, S.L. Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming. J. Immunol. 2018, 200, 3047–3052. [Google Scholar] [CrossRef] [Green Version]
- Misawa, T.; Takahama, M.; Kozaki, T.; Lee, H.; Zou, J.; Saitoh, T.; Akira, S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 2013, 14, 454–460. [Google Scholar] [CrossRef]
- Wang, Y.; Yang, C.; Mao, K.; Chen, S.; Meng, G.; Sun, B. Cellular localization of NLRP3 inflammasome. Protein Cell 2013, 4, 425–431. [Google Scholar] [CrossRef] [Green Version]
- Chen, J.; Chen, Z.J. PtdIns4P on dispersed trans -Golgi network mediates NLRP3 inflammasome activation. Nature 2018, 564, 71. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Meszaros, G.; He, W.; Xu, Y.; Magliarelli, H.d.F.; Mailly, L.; Mihlan, M.; Liu, Y.; Gámez, M.P.; Goginashvili, A.; et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J. Exp. Med. 2017, 214, 2671–2693. [Google Scholar] [CrossRef] [PubMed]
- Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.; et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010, 464, 1357–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cassel, S.L.; Eisenbarth, S.C.; Iyer, S.S.; Sadler, J.J.; Colegio, O.R.; Tephly, L.A.; Carter, A.B.; Rothman, P.B.; Flavell, R.A.; Sutterwala, F.S. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl. Acad. Sci. USA 2008, 105, 9035–9040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 2008, 9, 857–865. [Google Scholar] [CrossRef] [PubMed]
- Kool, M.; Pétrilli, V.; De Smedt, T.; Rolaz, A.; Hammad, H.; van Nimwegen, M.; Bergen, I.M.; Castillo, R.; Lambrecht, B.N.; Tschopp, J. Cutting edge: Alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. Baltim. Md 1950 2008, 181, 3755–3759. [Google Scholar] [CrossRef] [PubMed]
- Codolo, G.; Plotegher, N.; Pozzobon, T.; Brucale, M.; Tessari, I.; Bubacco, L.; de Bernard, M. Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies. PLoS ONE 2013, 8, e55375. [Google Scholar] [CrossRef] [PubMed]
- Dostert, C.; Guarda, G.; Romero, J.F.; Menu, P.; Gross, O.; Tardivel, A.; Suva, M.-L.; Stehle, J.-C.; Kopf, M.; Stamenkovic, I.; et al. Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal. PLoS ONE 2009, 4, e6510. [Google Scholar] [CrossRef]
- Orlowski, G.M.; Colbert, J.D.; Sharma, S.; Bogyo, M.; Robertson, S.A.; Rock, K.L. Multiple Cathepsins Promote Pro-IL-1β Synthesis and NLRP3-Mediated IL-1β Activation. J. Immunol. Baltim. Md 1950 2015, 195, 1685–1697. [Google Scholar] [CrossRef]
- Barlan, A.U.; Griffin, T.M.; McGuire, K.A.; Wiethoff, C.M. Adenovirus membrane penetration activates the NLRP3 inflammasome. J. Virol. 2011, 85, 146–155. [Google Scholar] [CrossRef]
- Hagar, J.A.; Powell, D.A.; Aachoui, Y.; Ernst, R.K.; Miao, E.A. Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock. Science 2013, 341, 1250–1253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kayagaki, N.; Wong, M.T.; Stowe, I.B.; Ramani, S.R.; Gonzalez, L.C.; Akashi-Takamura, S.; Miyake, K.; Zhang, J.; Lee, W.P.; Muszyński, A.; et al. Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4. Science 2013, 341, 1246–1249. [Google Scholar] [CrossRef] [PubMed]
- Balakrishnan, A.; Karki, R.; Berwin, B.; Yamamoto, M.; Kanneganti, T.-D. Guanylate binding proteins facilitate caspase-11-dependent pyroptosis in response to type 3 secretion system-negative Pseudomonas aeruginosa. Cell Death Discov. 2018, 4, 3. [Google Scholar] [CrossRef] [PubMed]
- Kayagaki, N.; Warming, S.; Lamkanfi, M.; Walle, L.V.; Louie, S.; Dong, J.; Newton, K.; Qu, Y.; Liu, J.; Heldens, S.; et al. Non-canonical inflammasome activation targets caspase-11. Nature 2011, 479, 117–121. [Google Scholar] [CrossRef] [PubMed]
- Baker, P.J.; Boucher, D.; Bierschenk, D.; Tebartz, C.; Whitney, P.G.; D’Silva, D.B.; Tanzer, M.C.; Monteleone, M.; Robertson, A.A.B.; Cooper, M.A.; et al. NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur. J. Immunol. 2015, 45, 2918–2926. [Google Scholar] [CrossRef] [PubMed]
- Shi, J.; Zhao, Y.; Wang, Y.; Gao, W.; Ding, J.; Li, P.; Hu, L.; Shao, F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014, 514, 187–192. [Google Scholar] [CrossRef]
- Broz, P.; Ruby, T.; Belhocine, K.; Bouley, D.M.; Kayagaki, N.; Dixit, V.M.; Monack, D.M. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012, 490, 288–291. [Google Scholar] [CrossRef] [PubMed]
- Pelegrin, P.; Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 2006, 25, 5071–5082. [Google Scholar] [CrossRef]
- Piccini, A.; Carta, S.; Tassi, S.; Lasiglié, D.; Fossati, G.; Rubartelli, A. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl. Acad. Sci. USA 2008, 105, 8067–8072. [Google Scholar] [CrossRef]
- Alves, L.A.; de Melo Reis, R.A.; de Souza, C.A.M.; de Freitas, M.S.; Teixeira, P.C.N.; Neto Moreira Ferreira, D.; Xavier, R.F. The P2X7 receptor: Shifting from a low- to a high-conductance channel—An enigmatic phenomenon? Biochim. Biophys. Acta BBA-Biomembr. 2014, 1838, 2578–2587. [Google Scholar] [CrossRef]
- Chu, L.H.; Indramohan, M.; Ratsimandresy, R.A.; Gangopadhyay, A.; Morris, E.P.; Monack, D.M.; Dorfleutner, A.; Stehlik, C. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat. Commun. 2018, 9, 996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Man, S.M.; Karki, R.; Sasai, M.; Place, D.E.; Kesavardhana, S.; Temirov, J.; Frase, S.; Zhu, Q.; Malireddi, R.K.S.; Kuriakose, T.; et al. IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes. Cell 2016, 167, 382–396.e17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meunier, E.; Dick, M.S.; Dreier, R.F.; Schürmann, N.; Kenzelmann Broz, D.; Warming, S.; Roose-Girma, M.; Bumann, D.; Kayagaki, N.; Takeda, K.; et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 2014, 509, 366–370. [Google Scholar] [CrossRef] [PubMed]
- Netea, M.G.; Nold-Petry, C.A.; Nold, M.F.; Joosten, L.A.B.; Opitz, B.; van der Meer, J.H.M.; van de Veerdonk, F.L.; Ferwerda, G.; Heinhuis, B.; Devesa, I.; et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood 2009, 113, 2324–2335. [Google Scholar] [CrossRef] [PubMed]
- Gaidt, M.M.; Ebert, T.S.; Chauhan, D.; Schmidt, T.; Schmid-Burgk, J.L.; Rapino, F.; Robertson, A.A.B.; Cooper, M.A.; Graf, T.; Hornung, V. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 2016, 44, 833–846. [Google Scholar] [CrossRef] [Green Version]
- 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. 2013, 190, 334–339. [Google Scholar] [CrossRef]
- Yang, J.; Liu, Z.; Xiao, T.S. Post-translational regulation of inflammasomes. Cell. Mol. Immunol. 2017, 14, 65–79. [Google Scholar] [CrossRef]
- Han, S.; Lear, T.B.; Jerome, J.A.; Rajbhandari, S.; Snavely, C.A.; Gulick, D.L.; Gibson, K.F.; Zou, C.; Chen, B.B.; Mallampalli, R.K. Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase. J. Biol. Chem. 2015, 290, 18124–18133. [Google Scholar] [CrossRef] [Green Version]
- Yan, Y.; Jiang, W.; Liu, L.; Wang, X.; Ding, C.; Tian, Z.; Zhou, R. Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome. Cell 2015, 160, 62–73. [Google Scholar] [CrossRef] [Green Version]
- Song, H.; Liu, B.; Huai, W.; Yu, Z.; Wang, W.; Zhao, J.; Han, L.; Jiang, G.; Zhang, L.; Gao, C.; et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat. Commun. 2016, 7, 13727. [Google Scholar] [CrossRef] [Green Version]
- Kawashima, A.; Karasawa, T.; Tago, K.; Kimura, H.; Kamata, R.; Usui-Kawanishi, F.; Watanabe, S.; Ohta, S.; Funakoshi-Tago, M.; Yanagisawa, K.; et al. ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages. J. Immunol. 2017, 199, 3614–3622. [Google Scholar] [CrossRef] [PubMed]
- Humphries, F.; Bergin, R.; Jackson, R.; Delagic, N.; Wang, B.; Yang, S.; Dubois, A.V.; Ingram, R.J.; Moynagh, P.N. The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome. Nat. Commun. 2018, 9, 1560. [Google Scholar] [CrossRef] [PubMed]
- Palazón-Riquelme, P.; Worboys, J.D.; Green, J.; Valera, A.; Martín-Sánchez, F.; Pellegrini, C.; Brough, D.; López-Castejón, G. USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep. 2018, 19, e44766. [Google Scholar] [CrossRef] [PubMed]
- Sandall, C.F.; MacDonald, J.A. Effects of phosphorylation on the NLRP3 inflammasome. Arch. Biochem. Biophys. 2019. [Google Scholar] [CrossRef] [PubMed]
- 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. 2016, 17, 1176–1186. [Google Scholar] [CrossRef] [PubMed]
- Guo, C.; Xie, S.; Chi, Z.; Zhang, J.; Liu, Y.; Zhang, L.; Zheng, M.; Zhang, X.; Xia, D.; Ke, Y.; et al. Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity 2016, 45, 802–816. [Google Scholar] [CrossRef] [PubMed]
- Spalinger, M.R.; Kasper, S.; Gottier, C.; Lang, S.; Atrott, K.; Vavricka, S.R.; Scharl, S.; Gutte, P.M.; Grütter, M.G.; Beer, H.-D.; et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J. Clin. Investig. 2016, 126, 1783–1800. [Google Scholar] [CrossRef] [Green Version]
- Stutz, A.; Kolbe, C.-C.; Stahl, R.; Horvath, G.L.; Franklin, B.S.; van Ray, O.; Brinkschulte, R.; Geyer, M.; Meissner, F.; Latz, E. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J. Exp. Med. 2017, 214, 1725–1736. [Google Scholar] [CrossRef]
- Hernandez-Cuellar, E.; Tsuchiya, K.; Hara, H.; Fang, R.; Sakai, S.; Kawamura, I.; Akira, S.; Mitsuyama, M. Cutting edge: Nitric oxide inhibits the NLRP3 inflammasome. J. Immunol. Baltim. Md 1950 2012, 189, 5113–5117. [Google Scholar] [CrossRef]
- Mao, K.; Chen, S.; Chen, M.; Ma, Y.; Wang, Y.; Huang, B.; He, Z.; Zeng, Y.; Hu, Y.; Sun, S.; et al. Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Cell Res. 2013, 23, 201–212. [Google Scholar] [CrossRef] [Green Version]
- Mishra, B.B.; Rathinam, V.A.K.; Martens, G.W.; Martinot, A.J.; Kornfeld, H.; Fitzgerald, K.A.; Sassetti, C.M. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat. Immunol. 2013, 14, 52–60. [Google Scholar] [CrossRef] [PubMed]
- Barry, R.; John, S.W.; Liccardi, G.; Tenev, T.; Jaco, I.; Chen, C.-H.; Choi, J.; Kasperkiewicz, P.; Fernandes-Alnemri, T.; Alnemri, E.; et al. SUMO-mediated regulation of NLRP3 modulates inflammasome activity. Nat. Commun. 2018, 9, 3001. [Google Scholar] [CrossRef] [PubMed]
- Bose, S.; Segovia, J.A.; Somarajan, S.R.; Chang, T.-H.; Kannan, T.R.; Baseman, J.B. ADP-Ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS Toxin Regulates Inflammasome Activity. mBio 2014, 5, e02186-14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mayor, A.; Martinon, F.; De Smedt, T.; Pétrilli, V.; Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat. Immunol. 2007, 8, 497–503. [Google Scholar] [CrossRef] [PubMed]
- Piippo, N.; Korhonen, E.; Hytti, M.; Skottman, H.; Kinnunen, K.; Josifovska, N.; Petrovski, G.; Kaarniranta, K.; Kauppinen, A. Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome. Sci. Rep. 2018, 8, 6720. [Google Scholar] [CrossRef] [PubMed]
- Li, F.; Song, X.; Su, G.; Wang, Y.; Wang, Z.; Qing, S.; Jia, J.; Wang, Y.; Huang, L.; Zheng, K.; et al. AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation. Biochem. Pharmacol. 2019, 166, 82–92. [Google Scholar] [CrossRef]
- Zuo, Y.; Wang, J.; Liao, F.; Yan, X.; Li, J.; Huang, L.; Liu, F. Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice. Front. Mol. Neurosci. 2018, 11, 401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, R.; Tardivel, A.; Thorens, B.; Choi, I.; Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 2010, 11, 136–140. [Google Scholar] [CrossRef]
- Masters, S.L.; Dunne, A.; Subramanian, S.L.; Hull, R.L.; Tannahill, G.M.; Sharp, F.A.; Becker, C.; Franchi, L.; Yoshihara, E.; Chen, Z.; et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 2010, 11, 897–904. [Google Scholar] [CrossRef]
- Shenoy, A.R.; Wellington, D.A.; Kumar, P.; Kassa, H.; Booth, C.J.; Cresswell, P.; MacMicking, J.D. GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals. Science 2012, 336, 481–485. [Google Scholar] [CrossRef]
- Man, S.M.; Karki, R.; Malireddi, R.K.S.; Neale, G.; Vogel, P.; Yamamoto, M.; Lamkanfi, M.; Kanneganti, T.-D. The transcription factor IRF1 and guanylate-binding proteins target AIM2 inflammasome activation by Francisella infection. Nat. Immunol. 2015, 16, 467–475. [Google Scholar] [CrossRef] [PubMed]
- Meunier, E.; Wallet, P.; Dreier, R.F.; Costanzo, S.; Anton, L.; Rühl, S.; Dussurgey, S.; Dick, M.S.; Kistner, A.; Rigard, M.; et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat. Immunol. 2015, 16, 476–484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lu, B.; Nakamura, T.; Inouye, K.; Li, J.; Tang, Y.; Lundbäck, P.; Valdes-Ferrer, S.I.; Olofsson, P.S.; Kalb, T.; Roth, J.; et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature 2012, 488, 670–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yoshida, K.; Okamura, H.; Hiroshima, Y.; Abe, K.; Kido, J.-I.; Shinohara, Y.; Ozaki, K. PKR induces the expression of NLRP3 by regulating the NF-κB pathway in Porphyromonas gingivalis-infected osteoblasts. Exp. Cell Res. 2017, 354, 57–64. [Google Scholar] [CrossRef] [PubMed]
- He, Y.; Franchi, L.; Núñez, G. The protein kinase PKR is critical for LPS-induced iNOS production but dispensable for inflammasome activation in macrophages. Eur. J. Immunol. 2013, 43, 1147–1152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, X.; Thome, S.; Ma, X.; Amrute-Nayak, M.; Finigan, A.; Kitt, L.; Masters, L.; James, J.R.; Shi, Y.; Meng, G.; et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nat. Commun. 2017, 8, 15986. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lang, T.; Lee, J.P.W.; Elgass, K.; Pinar, A.A.; Tate, M.D.; Aitken, E.H.; Fan, H.; Creed, S.J.; Deen, N.S.; Traore, D.A.K.; et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat. Commun. 2018, 9, 2223. [Google Scholar] [CrossRef]
- He, Y.; Zeng, M.Y.; Yang, D.; Motro, B.; Núñez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 2016, 530, 354–357. [Google Scholar] [CrossRef] [Green Version]
- Schmid-Burgk, J.L.; Chauhan, D.; Schmidt, T.; Ebert, T.S.; Reinhardt, J.; Endl, E.; Hornung, V. A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation. J. Biol. Chem. 2016, 291, 103–109. [Google Scholar] [CrossRef] [Green Version]
- Shi, H.; Wang, Y.; Li, X.; Zhan, X.; Tang, M.; Fina, M.; Su, L.; Pratt, D.; Bu, C.H.; Hildebrand, S.; et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 2016, 17, 250–258. [Google Scholar] [CrossRef]
- Salem, H.; Rachmin, I.; Yissachar, N.; Cohen, S.; Amiel, A.; Haffner, R.; Lavi, L.; Motro, B. Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy. Oncogene 2010, 29, 4046–4057. [Google Scholar] [CrossRef] [PubMed]
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Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci. 2019, 20, 3328. https://doi.org/10.3390/ijms20133328
Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. International Journal of Molecular Sciences. 2019; 20(13):3328. https://doi.org/10.3390/ijms20133328
Chicago/Turabian StyleKelley, Nathan, Devon Jeltema, Yanhui Duan, and Yuan He. 2019. "The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation" International Journal of Molecular Sciences 20, no. 13: 3328. https://doi.org/10.3390/ijms20133328