NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Limin Song, Lei Pei, Shanglong Yao, Yan Wu, You Shang, Limin Song, Lei Pei, Shanglong Yao, Yan Wu, You Shang

Abstract

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

Keywords: IL-18; IL-1β; NLRP3; astrocytes; inflammasome; microglia; neuroinflammation.

Figures

Figure 1
Figure 1
NLRP3 inflammasome: structure and function. The NLRP3 inflammasome mainly consists of the cytosolic sensor molecule NLRP3, the adaptor protein ASC, and the effector molecule pro-caspase-1. The assembly and activation of NLRP3 inflammasome results in caspase-1 activation. Activated caspase-1 subsequently leads to the maturation of IL-1β and IL-18, as well as mediates a form of inherent inflammatory cell death termed as pyroptosis. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; CARD, caspase activation and recruitment domain; GSDMD, gasdermin D; GSDMD-NT, gasdermin-N domain of GSDMD; IL, interleukin; LRR, leucine-rich repeat; NACHT (NOD), nucleotide binding and oligomerization domain; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; PYD, pyrin-only domain.
Figure 2
Figure 2
NLRP3 inflammasome activation-mediated neuroinflammation. Upon activation by a wide range of exogenous and endogenous stimuli, the NLRP3 inflammasome located in microglia and astrocytes trigger the maturation of IL-1β and IL-18 and induce pyroptotic cell death. The high levels IL-1β and IL-18 bind to their receptors on glial cells, neurons, macrophages and endothelial cells, as well as cooperate with other cytokines to initiate Th-cell signaling, thereby triggering a complex spectrum of signaling events, which results in exacerbation of inflammatory cascade responses within the central nervous system (CNS). Aβ, β-amyloid; ATP, adenosine triphosphate; BBB, blood–brain barrier; IL, interleukin; MSU, monosodium urate; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; Th, T helper.
Figure 3
Figure 3
Therapeutic approaches to targeting the NLRP3 inflammasome. The cartoon depicts the schematic mode of various therapeutic approaches described in detail in the text. Several steps in NLRP3 activation and the IL-1 pathway have been identified as targets for anti-neuroinflammatory therapies. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; BBG, brilliant blue G; BHB, β-hydroxybutyrate; IL, interleukin; IL-1R, interleukin-1 receptor; MNS, 3,4-methylenedioxy-β-nitrostyrene; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; P2X7R, P2X purinergic receptor 7; TLR, Toll-like receptor.

References

    1. Abo-Ouf H., Hooper A. W., White E. J., van Rensburg H. J., Trigatti B. L., Igdoura S. A. (2013). Deletion of tumor necrosis factor-α ameliorates neurodegeneration in Sandhoff disease mice. Hum. Mol. Genet. 22, 3960–3975. 10.1093/hmg/ddt250
    1. Adamczak S., Dale G., de Rivero Vaccari J. P., Bullock M. R., Dietrich W. D., Keane R. W. (2012). Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J. Neurosurg. 117, 1119–1125. 10.3171/2012.9.JNS12815
    1. Adamczak S. E., de Rivero Vaccari J. P., Dale G., Brand F. J., III., Nonner D., Bullock M. R., et al. . (2014). Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J. Cereb. Blood Flow Metab. 34, 621–629. 10.1038/jcbfm.2013.236
    1. Agostini L., Martinon F., Burns K., McDermott M. F., Hawkins P. N., Tschopp J. (2004). NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325. 10.1016/s1074-7613(04)00046-9
    1. Alfonso-Loeches S., Ureña-Peralta J. R., Morillo-Bargues M. J., Oliver-De La Cruz J., Guerri C. (2014). Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front. Cell. Neurosci. 8:216. 10.3389/fncel.2014.00216
    1. Alvarez J. I., Dodelet-Devillers A., Kebir H., Ifergan I., Fabre P. J., Terouz S., et al. . (2011). The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731. 10.1126/science.1206936
    1. Anderson M. A., Ao Y., Sofroniew M. V. (2014). Heterogeneity of reactive astrocytes. Neurosci. Lett. 565, 23–29. 10.1016/j.neulet.2013.12.030
    1. Anderson J. P., Mueller J. L., Rosengren S., Boyle D. L., Schaner P., Cannon S. B., et al. . (2004). Structural, expression and evolutionary analysis of mouse CIAS1. Gene 338, 25–34. 10.1016/j.gene.2004.05.002
    1. Aoki E., Yano R., Yokoyama H., Kato H., Araki T. (2009). Role of nuclear transcription factor kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine)-induced apoptosis in nigral neurons of mice. Exp. Mol. Pathol. 86, 57–64. 10.1016/j.yexmp.2008.10.004
    1. Arai T., Hasegawa M., Akiyama H., Ikeda K., Nonaka T., Mori H., et al. . (2006). TDP-43 is a component of ubiquitinpositive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611. 10.1016/j.bbrc.2006.10.093
    1. Arend W. P., Palmer G., Gabay C. (2008). IL-1, IL-18 and IL-33 families of cytokines. Immunol. Rev. 223, 20–38. 10.1111/j.1600-065X.2008.00624.x
    1. Ayers J. I., Schutt C. R., Shikiya R. A., Aguzzi A., Kincaid A. E., Bartz J. C. (2011). The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog. 7:e1001317. 10.1371/journal.ppat.1001317
    1. Bae H. R., Kim D. H., Park M. H., Lee B., Kim M. J., Lee E. K., et al. . (2016). β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget 7, 66444–66454. 10.18632/oncotarget.12119
    1. Barclay W., Shinohara M. L. (2017). Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Brain Pathol. 27, 213–219. 10.1111/bpa.12477
    1. Barreto G. E., Gonzalez J., Torres Y., Morales L. (2011). Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. Neurosci. Res. 71, 107–113. 10.1016/j.neures.2011.06.004
    1. Bauernfeind F. G., Horvath G., Stutz A., Alnemri E. S., MacDonald K., Speert D., et al. . (2009). Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791. 10.4049/jimmunol.0901363
    1. Becher B., Prat A., Antel J. P. (2000). Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia 29, 293–304. 10.1002/(SICI)1098-1136(20000215)29:4<293::AID-GLIA1>;2-1
    1. Bergsbaken T., Fink S. L., Cookson B. T. (2009). Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7, 99–109. 10.1038/nrmicro2070
    1. Bian L. H., Liu Y. F., Nichols L. T., Wang C. X., Wang Y. L., Liu G. F., et al. . (2012). Epidemiology of subarachnoid hemorrhage, patterns of management and outcomes in China: a hospital-based multicenter prospective study. CNS Neurosci. Ther. 18, 895–902. 10.1111/cns.12001
    1. Bossù P., Ciaramella A., Salani F., Vanni D., Palladino I., Caltagirone C., et al. . (2010). Interleukin-18, from neuroinflammation to Alzheimer’s disease. Curr. Pharm. Des. 16, 4213–4224. 10.2174/138161210794519147
    1. Brown A. M., Ransom B. R. (2007). Astrocyte glycogen and brain energy metabolism. Glia 55, 1263–1267. 10.1002/glia.20557
    1. Bruchard M., Mignot G., Derangère V., Chalmin F., Chevriaux A., Végran F., et al. . (2013). Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64. 10.1038/nm.2999
    1. Byrnes K. R., Faden A. I. (2007). Role of cell cycle proteins in CNS injury. Neurochem. Res. 32, 1799–1807. 10.1007/s11064-007-9312-2
    1. Cannon J. G. (2000). Inflammatory cytokines in nonpathological states. News Physiol. Sci. 15, 298–303.
    1. Chen X., He W. T., Hu L., Li J., Fang Y., Wang X., et al. . (2016). Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 26, 1007–1020. 10.1038/cr.2016.100
    1. Chen S., Ma Q., Krafft P. R., Hu Q., Rolland W., II., Sherchan P., et al. . (2013). P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH. Neurobiol. Dis. 58, 296–307. 10.1016/j.nbd.2013.06.011
    1. Cherry J. D., Olschowka J. A., O’Banion M. K. (2014). Neuroinflammation and M2 microglia: the good, the bad and the inflamed. J. Neuroinflammation 11:98. 10.1186/1742-2094-11-98
    1. Cho M. H., Cho K., Kang H. J., Jeon E. Y., Kim H. S., Kwon H. J., et al. . (2014). Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy 10, 1761–1775. 10.4161/auto.29647
    1. Choi D. Y., Liu M., Hunter R. L., Cass W. A., Pandya J. D., Sullivan P. G., et al. . (2009). Striatal neuroinflammation promotes Parkinsonism in rats. PLoS One 4:e5482. 10.1371/journal.pone.0005482
    1. Chuang Y. T., Lin Y. C., Lin K. H., Chou T. F., Kuo W. C., Yang K. T., et al. . (2011). Tumor suppressor death-associated protein kinase is required for full IL-1β production. Blood 117, 960–970. 10.1182/blood-2010-08-303115
    1. Cocco M., Garella D., Di Stilo A., Borretto E., Stevanato L., Giorgis M., et al. . (2014). Electrophilic warhead-based design of compounds preventing NLRP3 inflammasome-dependent pyroptosis. J. Med. Chem. 57, 10366–10382. 10.1021/jm501072b
    1. Coll R. C., Robertson A., Butler M., Cooper M., O’Neill L. A. (2011). The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS One 6:e29539. 10.1371/journal.pone.0029539
    1. Coll R. C., Robertson A. A., Chae J. J., Higgins S. C., Muñoz-Planillo R., Inserra M. C., et al. . (2015). A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255. 10.1038/nm.3806
    1. Court H., Volans G. N. (1984). Poisoning after overdose with non-steroidal anti-inflammatory drugs. Adverse Drug React. Acute Poisoning Rev. 3, 1–21.
    1. Cregg J. M., DePaul M. A., Filous A. R., Lang B. T., Tran A., Silver J. (2014). Functional regeneration beyond the glial scar. Exp. Neurol. 253, 197–207. 10.1016/j.expneurol.2013.12.024
    1. Daniels M. J., Rivers-Auty J., Schilling T., Spencer N. G., Watremez W., Fasolino V., et al. . (2016). Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat. Commun. 7:12504. 10.1038/ncomms12504
    1. David S., Kroner A. (2011). Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388–399. 10.1038/nrn3053
    1. de Almeida L., Khare S., Misharin A. V., Patel R., Ratsimandresy R. A., Wallin M. C., et al. . (2015). The PYRIN domain-only protein POP1 inhibits inflammasome assembly and ameliorates inflammatory disease. Immunity 43, 264–276. 10.1016/j.immuni.2015.07.018
    1. de Jong B. A., Huizinga T. W., Bollen E. L., Uitdehaag B. M., Bosma G. P., van Buchem M. A., et al. . (2002). Production of IL-1β and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis. J. Neuroinflammation 126, 172–179. 10.1016/s0165-5728(02)00056-5
    1. de Rivero Vaccari J. P., Brand F., III., Adamczak S., Lee S. W., Perez-Barcena J., Wang M. Y., et al. . (2016). Exosome-mediated inflammasome signaling after central nervous system injury. J. Neurochem. 136, 39–48. 10.1111/jnc.13036
    1. de Rivero Vaccari J. P., Lotocki G., Alonso O. F., Bramlett H. M., Dietrich W. D., Keane R. W. (2009). Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J. Cereb. Blood Flow Metab. 29, 1251–1261. 10.1038/jcbfm.2009.46
    1. Debye B., Schmülling L., Zhou L., Rune G., Beyer C., Johann S. (2016). Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice. Brain Pathol. [Epub ahead of print]. 10.1111/bpa.12467
    1. Demento S. L., Eisenbarth S. C., Foellmer H. G., Platt C., Caplan M. J., Mark Saltzman W., et al. . (2009). Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. Vaccine 27, 3013–3021. 10.1016/j.vaccine.2009.03.034
    1. Dempsey C., Rubio Araiz A., Bryson K. J., Finucane O., Larkin C., Mills E. L., et al. . (2017). 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. 10.1016/j.bbi.2016.12.014
    1. Deplano S., Cook H. T., Russell R., Franchi L., Schneiter S., Bhangal G., et al. . (2013). P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis. J. Leukoc. Biol. 93, 127–134. 10.1189/jlb.0612284
    1. Diaz-Hernandez J. I., Gomez-Villafuertes R., León-Otegui M., Hontecillas-Prieto L., Del Puerto A., Trejo J. L., et al. . (2012). In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer’s disease through GSK3β and secretases. Neurobiol. Aging 33, 1816–1828. 10.1016/j.neurobiolaging.2011.09.040
    1. Dinarello C. A., Simon A., van der Meer J. W. (2012). Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633–652. 10.1038/nrd3800
    1. Ding J., Wang K., Liu W., She Y., Sun Q., Shi J., et al. . (2016). Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 573, 111–116. 10.1038/nature18590
    1. Dowds T. A., Masumoto J., Zhu L., Inohara N., Núñez G. (2004). Cryopyrin-induced interleukin 1β secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. J. Biol. Chem. 279, 21924–21928. 10.1074/jbc.M401178200
    1. Dumas A., Amiable N., de Rivero Vaccari J. P., Chae J. J., Keane R. W., Lacroix S., et al. . (2014). The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis. PLoS Pathog. 10:e1004150. 10.1371/journal.ppat.1004150
    1. Duncan J. A., Bergstralh D. T., Wang Y., Willingham S. B., Ye Z., Zimmermann A. G., et al. . (2007). Cryopyrin/NALP3 binds ATP/dATP, is an ATPase and requires ATP binding to mediate inflammatory signaling. Proc. Natl. Acad. Sci. U S A 104, 8041–8046. 10.1073/pnas.0611496104
    1. Duncan J. A., Gao X., Huang M. T., O’Connor B. P., Thomas C. E., Willingham S. B., et al. . (2009). Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J. Immunol. 182, 6460–6469. 10.4049/jimmunol.0802696
    1. Efferth T., Kaina B. (2010). Toxicity of the antimalarial artemisinin and its dervatives. Crit. Rev. Toxicol. 40, 405–421. 10.3109/10408441003610571
    1. Ellis A., Grace P. M., Wieseler J., Favret J., Springer K., Skarda B., et al. . (2016). Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav. Immun. 58, 348–356. 10.1016/j.bbi.2016.08.004
    1. Elmore M. R., Burton M. D., Conrad M. S., Rytych J. L., Van Alstine W. G., Johnson R. W. (2014). Respiratory viral infection in neonatal piglets causes marked microglia activation in the hippocampus and deficits in spatial learning. J. Neurosci. 34, 2120–2129. 10.1523/JNEUROSCI.2180-13.2014
    1. Fann D. Y., Lee S. Y., Manzanero S., Chunduri P., Sobey C. G., Arumugam T. V. (2013a). Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res. Rev. 12, 941–966. 10.1016/j.arr.2013.09.004
    1. Fann D. Y., Lee S. Y., Manzanero S., Tang S. C., Gelderblom M., Chunduri P., et al. . (2013b). Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 4:e790. 10.1038/cddis.2013.326
    1. Felderhoff-Mueser U., Schmidt O. I., Oberholzer A., Bührer C., Stahel P. F. (2005). IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci. 28, 487–493. 10.1016/j.tins.2005.06.008
    1. Fellner L., Irschick R., Schanda K., Reindl M., Klimaschewski L., Poewe W., et al. . (2013). Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360. 10.1002/glia.22437
    1. Feng L., Chen Y., Ding R., Fu Z., Yang S., Deng X., et al. . (2015). P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J. Neuroinflammation 12:190. 10.1186/s12974-015-0409-2
    1. Ferrante C. J., Pinhal-Enfield G., Elson G., Cronstein B. N., Hasko G., Outram S., et al. . (2013). The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation 36, 921–931. 10.1007/s10753-013-9621-3
    1. Ferrari C. C., Depino A. M., Prada F., Muraro N., Campbell S., Podhajcer O., et al. . (2004). Reversible demyelination, blood-brain barrier breakdown and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain. Am. J. Pathol. 165, 1827–1837. 10.1016/s0002-9440(10)63438-4
    1. Feske S., Skolnik E. Y., Prakriya M. (2012). Ion channels and transporters in lymphocyte function and immunity. Nat. Rev. Immunol. 12, 532–547. 10.1038/nri3233
    1. Fink S. L., Bergsbaken T., Cookson B. T. (2008). Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. U S A 105, 4312–4317. 10.1073/pnas.0707370105
    1. Fogal B., Li J., Lobner D., McCullough L. D., Hewett S. J. (2007). System xc– activity and astrocytes are necessary for interleukin-1 β-mediated hypoxic neuronal injury. J. Neurosci. 27, 10094–10105. 10.1523/JNEUROSCI.2459-07.2007
    1. Fontalba A., Gutiérrez O., Llorca J., Mateo I., Berciano J., Fernández-Luna J. L., et al. . (2008). Deficiency of CARD8 is associated with increased Alzheimer’s disease risk in women. Dement. Geriatr. Cogn. Disord. 26, 247–250. 10.1159/000160956
    1. Franco R., Fernández-Suárez D. (2015). Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131, 65–86. 10.1016/j.pneurobio.2015.05.003
    1. Franke H., Günther A., Grosche J., Schmidt R., Rossner S., Reinhardt R., et al. . (2004). P2X7 receptor expression after ischemia in the cerebral cortex of rats. J. Neuropathol. Exp. Neurol. 63, 686–699. 10.1093/jnen/63.7.686
    1. Frank J. J., Wightkin W. T., Hubner J. W. (1983). Acute toxicity of nonsteroidal antiinflammatory agents: seizure following a mefenamic acid overdose. Drug Intell. Clin. Pharm. 17, 204–205. 10.1177/106002808301700309
    1. Fu R., Shen Q., Xu P., Luo J. J., Tang Y. (2014). Phagocytosis of microglia in the central nervous system diseases. Mol. Neurobiol. 49, 1422–1434. 10.1007/s12035-013-8620-6
    1. Geissmann F., Gordon S., Hume D. A., Mowat A. M., Randolph G. J. (2010). Unravelling mononuclear phagocyte heterogeneity. Nat. Rev. Immunol. 10, 453–460. 10.1038/nri2784
    1. Geldhoff M., Mook-Kanamori B. B., Brouwer M. C., Troost D., Leemans J. C., Flavell R. A., et al. . (2013a). Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis. BMC Infect. Dis. 13:358. 10.1186/1471-2334-13-358
    1. Geldhoff M., Mook-Kanamori B. B., Brouwer M. C., Valls Seron M., Baas F., van der Ende A., et al. . (2013b). Genetic variation in inflammasome genes is associated with outcome in bacterial meningitis. Immunogenetics 65, 9–16. 10.1007/s00251-012-0653-x
    1. Gosselin D., Rivest S. (2007). Role of IL-1 and TNF in the brain: twenty years of progress on a Dr. Jekyll/Mr. Hyde duality of the innate immune system. Brain Behav. Immun. 21, 281–289. 10.1016/j.bbi.2006.12.004
    1. Gris D., Ye Z., Iocca H. A., Wen H., Craven R. R., Gris P., et al. . (2010). NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974–981. 10.4049/jimmunol.0904145
    1. Halle A., Hornung V., Petzold G. C., Stewart C. R., Monks B. G., Reinhecke L. T., et al. . (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865. 10.1038/ni.1636
    1. Hanamsagar R., Torres V., Kielian T. (2011). Inflammasome activation and IL-1β/IL-18 processing are influenced by distinct pathways in microglia. J. Neurochem. 119, 736–748. 10.1111/j.1471-4159.2011.07481.x
    1. Harari O. A., Liao J. K. (2010). NF-κB and innate immunity in ischemic stroke. Ann. N Y Acad. Sci. 1207, 32–40. 10.1111/j.1749-6632.2010.05735.x
    1. He Y., Amer A. O. (2014). Microbial modulation of host apoptosis and pyroptosis. Front. Cell. Infect. Microbiol. 4:83. 10.3389/fcimb.2014.00083
    1. He Y., Zeng M. Y., Yang D., Motro B., Núñez G. (2016). NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357. 10.1038/nature16959
    1. Heneka M. T., O’Banion M. K. (2007). Inflammatory processes in Alzheimer’s disease. J. Neuroimmunol. 184, 69–91. 10.1016/j.jneuroim.2006.11.017
    1. Heneka M. T., Kummer M. P., Latz E. (2014). Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477. 10.1038/nri3705
    1. Heneka M. T., Kummer M. P., Stutz A., Delekate A., Schwartz S., Vieira-Saecker A., et al. . (2013). NLRP3 is activated in Alzheimer’ disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678. 10.1038/nature11729
    1. Hernandez-Cuellar E., Tsuchiya K., Hara H., Fang R., Sakai S., Kawamura I., et al. . (2012). Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. J. Immunol. 189, 5113–5117. 10.4049/jimmunol.1202479
    1. Hoegen T., Tremel N., Klein M., Angele B., Wagner H., Kirschning C., et al. . (2011). The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATPdependent lysosomal cathepsin B release. J. Immunol. 187, 5540–5551. 10.4049/jimmunol.1100790
    1. Hoffman H. M., Scott P., Mueller J. L., Misaghi A., Stevens S., Yancopoulos G. D., et al. . (2010). Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice. Arthritis Rheum. 62, 2170–2179. 10.1002/art.27456
    1. Hornung V., Bauernfeind F., Halle A., Samstad E. O., Kono H., Rock K. L., et al. . (2008). Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856. 10.1038/ni.1631
    1. Hsieh P. W., Chang Y. T., Chuang W. Y., Shih H. C., Chiang S. Z., Wu C. C. (2010). The synthesis and biologic evaluation of anti-platelet and cytotoxic β-nitrostyrenes. Bioorg. Med. Chem. 18, 7621–7627. 10.1016/j.bmc.2010.08.039
    1. Hu X., Liu G., Hou Y., Shi J., Zhu L., Jin D., et al. . (2012). Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells. Cell. Mol. Immunol. 9, 464–472. 10.1038/cmi.2012.47
    1. Hu S., Sheng W. S., Ehrlich L. C., Peterson P. K., Chao C. C. (2000). Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7, 153–159. 10.1159/000026433
    1. Huang W. X., Huang P., Hillert J. (2004). Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis. Mult. Scler. 10, 482–487. 10.1191/1352458504ms1071oa
    1. Inoue M., Williams K. L., Gunn M. D., Shinohara M. L. (2012). NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U S A 109, 10480–10485. 10.1073/pnas.1201836109
    1. Ioannides Z. A., Henderson R. D., Robertson T., Davis M., McCombe P. A. (2016). When does ALS start? A novel SOD-1 p.Gly142Arg mutation causing motor neurone disease with prominent premorbid cramps and spasms. J. Neurol. Neurosurg. Psychiatry 87, 1031–1032. 10.1136/jnnp-2015-311582
    1. Ito U., Nagasao J., Kawakami E., Oyanagi K. (2007). Fate of disseminated dead neurons in the cortical ischemic penumbra: ultrastructure indicating a novel scavenger mechanism of microglia and astrocytes. Stroke 38, 2577–2583. 10.1161/STROKEAHA.107.484394
    1. Ito M., Shichita T., Okada M., Komine R., Noguchi Y., Yoshimura A., et al. . (2015). Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat. Commun. 6:7360. 10.1038/ncomms8360
    1. Jha S., Srivastava S. Y., Brickey W. J., Iocca H., Toews A., Morrison J. P., et al. . (2010). The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J. Neurosci. 30, 15811–15820. 10.1523/JNEUROSCI.4088-10.2010
    1. Ji J., Kline A. E., Amoscato A., Samhan-Arias A. K., Sparvero L. J., Tyurin V. A., et al. . (2012). Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nat. Neurosci. 15, 1407–1413. 10.1038/nn.3195
    1. Jian Z., Ding S., Deng H., Wang J., Yi W., Wang L., et al. . (2016). Probenecid protects against oxygen-glucose deprivation injury in primary astrocytes by regulating inflammasome activity. Brain Res. 1643, 123–129. 10.1016/j.brainres.2016.05.002
    1. Jiang W., Huang Y., He F., Liu J., Li M., Sun T., et al. . (2016). Dopamine D1 receptor agonist A-68930 inhibits NLRP3 inflammasome activation, controls Inflammation, and alleviates histopathology in a rat model of spinal cord injury. Spine (Phila Pa 1976) 41, E330–E334. 10.1097/BRS.0000000000001287
    1. Johann S., Heitzer M., Kanagaratnam M., Goswami A., Rizo T., Weis J., et al. . (2015). NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63, 2260–2273. 10.1002/glia.22891
    1. Juliana C., Fernandes-Alnemri T., Kang S., Farias A., Qin F., Alnemri E. S. (2012). Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem. 287, 36617–36622. 10.1074/jbc.M112.407130
    1. Kamour A., Crichton S., Cooper G., Lupton D. J., Eddleston M., Vale J. A., et al. . (2016). Central nervous system toxicity of mefenamic acid overdose compared with other NSAIDs: an analysis of cases reported to the United Kingdom National Poisons Information Service. Br. J. Clin. Pharmacol. [Epub ahead of print]. 10.1111/bcp.13169
    1. Kanneganti T. D., Body-Malapel M., Amer A., Park J. H., Whitfield J., Franchi L., et al. . (2006a). Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J. Biol. Chem. 281, 36560–36568. 10.1074/jbc.M607594200
    1. Kanneganti T. D., Ozören N., Body-Malapel M., Amer A., Park J. H., Franchi L., et al. . (2006b). Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236. 10.1038/nature04517
    1. Karmakar M., Katsnelson M. A., Dubyak G. R., Pearlman E. (2016). Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat. Commun. 7:10555. 10.1038/ncomms10555
    1. Karve I. P., Taylor J. M., Crack P. J. (2016). The contribution of astrocytes and microglia to traumatic brain injury. Br. J. Pharmacol. 173, 692–702. 10.1111/bph.13125
    1. Kaushal V., Dye R., Pakavathkumar P., Foveau B., Flores J., Hyman B., et al. . (2015). Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-β production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 22, 1676–1686. 10.1038/cdd.2015.16
    1. Kaushik D. K., Gupta M., Kumawat K. L., Basu A. (2012). NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis. PLoS One 7:e32270. 10.1371/journal.pone.0032270
    1. Keep R. F., Hua Y., Xi G. (2012). Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 11, 720–731. 10.1016/s1474-4422(12)70104-7
    1. Keller M., Rüegg A., Werner S., Beer H. D. (2008). Active caspase-1 is a regulator of unconventional protein secretion. Cell 32, 818–831. 10.1016/j.cell.2007.12.040
    1. Kettenmann H., Hanisch U.-K., Noda M., Verkhratsky A. (2011). Physiology of microglia. Physiol. Rev. 91, 461–553. 10.1152/physrev.00011.2010
    1. Kierdorf K., Erny D., Goldmann T., Sander V., Schulz C., Perdiguero E. G., et al. . (2013). Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280. 10.1038/nn.3318
    1. Kim J.-Y., Paton J. C., Briles D. E., Rhee D.-K., Pyo S. (2015). Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia. Oncotarget 6, 44161–44178. 10.18632/oncotarget.6592
    1. Kingswell R. S. (1981). Mefenamic acid overdose. Lancet 2:307. 10.1016/s0140-6736(81)90554-7
    1. Koedel U., Frankenberg T., Kirschnek S., Obermaier B., Häcker H., Paul R., et al. . (2009). Apoptosis is essential for neutrophil functional shutdown and determines tissue damage in experimental pneumococcal meningitis. PLoS Pathog. 5:e1000461. 10.1371/journal.ppat.1000461
    1. Kuemmerle-Deschner J. B., Hachulla E., Cartwright R., Hawkins P. N., Tran T. A., Bader-Meunier B., et al. . (2011). Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann. Rheum. Dis. 70, 2095–2102. 10.1136/ard.2011.152728
    1. Kumar A., Barrett J. P., Alvarez-Croda D. M., Stoica B. A., Faden A. I., Loane D. J. (2016). NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. Brain Behav. Immun. 58, 291–309. 10.1016/j.bbi.2016.07.158
    1. Kumar H., Kawai T., Akira S. (2011). Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34. 10.3109/08830185.2010.529976
    1. Lalancette-Hébert M., Gowing G., Simard A., Weng Y. C., Kriz J. (2007). Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci. 27, 2596–2605. 10.1523/JNEUROSCI.5360-06.2007
    1. Lamkanfi M., Mueller J. L., Vitari A. C., Misaghi S., Fedorova A., Deshayes K., et al. . (2009). Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187, 61–70. 10.1083/jcb.200903124
    1. Lammerding L., Slowik A., Johann S., Beyer C., Zendedel A. (2016). Post-stroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology 103, 460–475. 10.1159/000439435
    1. Lazovic J., Basu A., Lin H.-W., Rothstein R. P., Krady J. K., Smith M. B., et al. . (2005). Neuroinflammation and both cytotoxic and vasogenic edema are reduced in interleukin-1 type 1 receptor-deficient mice conferring neuroprotection. Stroke 36, 2226–2231. 10.1161/01.str.0000182255.08162.6a
    1. Lee H. M., Kang J., Lee S. J., Jo E. K. (2013). Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria. Glia 61, 441–452. 10.1002/glia.22448
    1. Lee G. S., Subramanian N., Kim A. I., Aksentijevich I., Goldbach-Mansky R., Sacks D. B., et al. . (2012). The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123–127. 10.1038/nature11588
    1. Levin H. S., Diaz-Arrastia R. R. (2015). Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol. 14, 506–517. 10.1016/s1474-4422(15)00002-2
    1. Li J., Chen J., Mo H., Chen J., Qian C., Yan F., et al. . (2016). Minocycline protects against NLRP3 inflammasome-induced inflammation and p53-associated apoptosis in early brain injury after subarachnoid hemorrhage. Mol. Neurobiol. 53, 2668–2678. 10.1007/s12035-015-9318-8
    1. Li Q., Hickman M. (2011). Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine and predict the neurotoxicity of artemisinins. Toxicology 279, 1–9. 10.1016/j.tox.2010.09.005
    1. Li D., Wang C., Yao Y., Chen L., Liu G., Zhang R., et al. . (2016). mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J. 30, 3388–3399. 10.1096/fj.201600495r
    1. Licastro F., Pedrini S., Caputo L., Annoni G., Davis L. J., Ferri C., et al. . (2000). Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J. Neuroimmunol. 103, 97–102. 10.1016/s0165-5728(99)00226-x
    1. Liepinsh E., Barbals R., Dahl E., Sharipo A., Staub E., Otting G. (2003). The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J. Mol. Biol. 332, 1155–1163. 10.1016/j.jmb.2003.07.007
    1. Lin C., Chao H., Li Z., Xu X., Liu Y., Bao Z., et al. . (2017). Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Exp. Neurol. 290, 115–122. 10.1016/j.expneurol.2017.01.005
    1. Liu B., Le K. X., Park M. A., Wang S., Belanger A. P., Dubey S., et al. . (2015). In vivo detection of age- and disease-related Increases in neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in wild-type and Alzheimer’s transgenic mice. J. Neurosci. 35, 15716–15730. 10.1523/JNEUROSCI.0996-15.2015
    1. Liu H.-D., Li W., Chen Z.-R., Hu Y.-C., Zhang D.-D., Shen W., et al. . (2013). Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem. Res. 38, 2072–2083. 10.1007/s11064-013-1115-z
    1. Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V. G., Wu H., et al. . (2016). Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158. 10.1038/nature18629
    1. Loane D. J., Byrnes K. R. (2010). Role of microglia in neurotrauma. Neurotherapeutics 7, 366–377. 10.1016/j.nurt.2010.07.002
    1. Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbäck P., et al. . (2012). Novel role of PKR in inflammasome activation and HMGB1 release. Nature 488, 670–674. 10.1038/nature11290
    1. Lu M., Sun X. L., Qiao C., Liu Y., Ding J. H., Hu G. (2014). Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol. Aging 35, 421–430. 10.1016/j.neurobiolaging.2013.08.015
    1. Ma Q., Chen S., Hu Q., Feng H., Zhang J. H., Tang J. (2014). NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann. Neurol. 75, 209–219. 10.1002/ana.24070
    1. Ma J., Xiao W., Wang J., Wu J., Ren J., Hou J., et al. . (2016). Propofol inhibits NLRP3 inflammasome and attenuates blast-Induced traumatic brain injury in rats. Inflammation 39, 2094–2103. 10.1007/s10753-016-0446-8
    1. Mamik M. K., Hui E., Branton W. G., McKenzie B. A., Chisholm J., Cohen E. A., et al. . (2016). HIV-1 viral protein R activates NLRP3 inflammasome in microglia: implications for HIV-1 associated neuroinflammation. J. Neuroimmune Pharmacol. [Epub ahead of print]. 10.1007/s11481-016-9708-3
    1. Marchetti C., Chojnacki J., Toldo S., Mezzaroma E., Tranchida N., Rose S. W., et al. . (2014). A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse. J. Cardiovasc. Pharmacol. 63, 316–322. 10.1097/FJC.0000000000000053
    1. Mariathasan S., Weiss D. S., Newton K., McBride J., O’Rourke K., Roose-Girma M., et al. . (2006). Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232. 10.1038/nature04515
    1. Marina-García N., Franchi L., Kim Y. G., Miller D., McDonald C., Boons G. J., et al. . (2008). Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. J. Immunol. 180, 4050–4057. 10.4049/jimmunol.180.6.4050
    1. Martinon F., Burns K., Tschopp J. (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426. 10.1016/S1097-2765(02)00599-3
    1. Martinon F., Pétrilli V., Mayor A., Tardivel A., Tschopp J. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241. 10.1038/nature04516
    1. Masters S. L., Dunne A., Subramanian S. L., Hull R. L., Tannahill G. M., Sharp F. A., et al. . (2010). 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. 10.1038/ni.1935
    1. Mastrocola R., Penna C., Tullio F., Femminò S., Nigro D., Chiazza F., et al. . (2016). Pharmacological inhibition of NLRP3 inflammasome attenuates myocardial ischemia/reperfusion injury by activation of RISK and mitochondrial pathways. Oxid. Med. Cell. Longev. 2016:5271251. 10.1155/2016/5271251
    1. Masumoto J., Taniguchi S., Ayukawa K., Sarvotham H., Kishino T., Niikawa N., et al. . (1999). ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J. Biol. Chem. 274, 33835–33838. 10.1074/jbc.274.48.33835
    1. Mawhinney L. J., de Rivero Vaccari J. P., Dale G. A., Keane R. W., Bramlett H. M. (2011). Heightened inflammasome activation is linked to age-related cognitive impairment in Fischer 344 rats. BMC Neurosci. 12:123. 10.1186/1471-2202-12-123
    1. McAfoose J., Baune B. T. (2009). Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 33, 355–366. 10.1016/j.neubiorev.2008.10.005
    1. McAuley J. L., Tate M. D., MacKenzie-Kludas C. J., Pinar A., Zeng W., Stutz A., et al. . (2013). Activation of the NLRP3 inflammasome by IAV virulence protein PB1–F2 contributes to severe pathophysiology and disease. PLoS Pathog. 9:e1003392. 10.1371/journal.ppat.1003392
    1. Meissner F., Molawi K., Zychlinsky A. (2010). Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis. Proc. Natl. Acad. Sci. U S A 107, 13046–13050. 10.1073/pnas.1002396107
    1. Meng G., Grabiec A., Vallon M., Ebe B., Hampel S., Bessler W., et al. . (2003). Cellular recognition of tri-/di-palmitoylated peptides is independent from a domain encompassing the N-terminal seven leucine-rich repeat (LRR)/LRR-like motifs of TLR2. J. Biol. Chem. 278, 39822–39829. 10.1074/jbc.m304766200
    1. Michell-Robinson M. A., Touil H., Healy L. M., Owen D. R., Durafourt B. A., Bar-Or A., et al. . (2015). Roles of microglia in brain development, tissue maintenance and repair. Brain 138, 1138–1159. 10.1093/brain/awv066
    1. Mishra B. B., Rathinam V. A., Martens G. W., Martinot A. J., Kornfeld H., Fitzgerald K. A., et al. . (2013). Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat. Immunol. 14, 52–60. 10.1038/ni.2474
    1. Mitchell A. J., Yau B., McQuillan J. A., Ball H. J., Too L. K., Abtin A., et al. . (2012). Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis. J. Immunol. 189, 4970–4980. 10.4049/jimmunol.1201687
    1. Miwa T., Furukawa S., Nakajima K., Furukawa Y., Kohsaka S. (1997). Lipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia. J. Neurosci. Res. 50, 1023–1029. 10.1002/(SICI)1097-4547(19971215)50:6<1023::AID-JNR13>;2-S
    1. Moss D. W., Bates T. E. (2001). Activation of murine microglial cell lines by lipopolysaccharide and interferon-γ causes NO-mediated decreases in mitochondrial and cellular function. Eur. J. Neurosci. 13, 529–538. 10.1046/j.1460-9568.2001.01418.x
    1. Murakami T., Ockinger J., Yu J., Byles V., McColl A., Hofer A. M., et al. . (2012). Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl. Acad. Sci. U S A 109, 11282–11287. 10.1073/pnas.1117765109
    1. Nakahira M., Ahn H. J., Park W. R., Gao P., Tomura M., Park C. S., et al. . (2002). Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J. Immunol. 168, 1146–1153. 10.4049/jimmunol.168.3.1146
    1. Nayak D., Roth T. L., McGavern D. B. (2014). Microglia development and function. Annu. Rev. Immunol. 32, 367–402. 10.1146/annurev-immunol-032713-120240
    1. Newman Z. L., Crown D., Leppla S. H., Moayeri M. (2010). Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages. Biochem. Biophys. Res. Commun. 398, 785–789. 10.1016/j.bbrc.2010.07.039
    1. Nuvolone M., Sorce S., Schwarz P., Aguzzi A. (2015). Prion pathogenesis in the absence of NLRP3/ASC inflammasomes. PLoS One 10:e0117208. 10.1371/journal.pone.0117208
    1. O’Connor W. J., Harton J. A., Zhu X., Linhoff M. W., Ting J. P. (2003). Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-κ B suppressive properties. J. Immunol. 171, 6329–6333. 10.4049/jimmunol.171.12.6329
    1. Orhan N., Ugur Yilmaz C., Ekizoglu O., Ahishali B., Kucuk M., Arican N., et al. . (2015). Effects of β-hydroxybutyrate on brain vascular permeability in rats with traumatic brain injury. Brain Res. 1631, 113–126. 10.1016/j.brainres.2015.11.038
    1. Orihuela R., McPherson C. A., Harry G. J. (2016). Microglial M1/M2 polarization and metabolic states. Br. J. Pharmacol. 173, 649–665. 10.1111/bph.13139
    1. Paolicelli R. C., Bolasco G., Pagani F., Maggi L., Scianni M., Panzanelli P., et al. . (2012). Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458. 10.1126/science.1202529
    1. Parajuli B., Sonobe Y., Horiuchi H., Takeuchi H., Mizuno T., Suzumura A. (2013). Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer’s disease. Cell Death Dis. 4:e975. 10.1038/cddis.2013.503
    1. Pekny M., Nilsson M. (2005). Astrocyte activation and reactive gliosis. Glia 50, 427–434. 10.1002/glia.20207
    1. Perea G., Navarrete M., Araque A. (2009). Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 32, 421–431. 10.1016/j.tins.2009.05.001
    1. Perea G., Sur M., Araque A. (2014). Neuron-glia networks: integral gear of brain function. Front. Cell. Neurosci. 8:378. 10.3389/fncel.2014.00378
    1. Pétrilli V., Papin S., Dostert C., Mayor A., Martinon F., Tschopp J. (2007). Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589. 10.1038/sj.cdd.4402195
    1. Pinar A., Dowling J. K., Bitto N. J., Robertson A. B., Latz E., Stewart C. R., et al. . (2016). PB1–F2 derived from avian influenza a virus H7N9 induces inflammation via activation of the NLRP3 inflammasome. J. Biol. Chem. 292, 826–836. 10.1074/jbc.M116.756379
    1. Py B. F., Kim M. S., Vakifahmetoglu-Norberg H., Yuan J. (2013). Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 49, 331–338. 10.1016/j.molcel.2012.11.009
    1. Qin M., Landriscina A., Rosen J. M., Wei G., Kao S., Olcott W., et al. . (2015). Nitric Oxide-releasing nanoparticles prevent propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J. Invest. Dermatol. 135, 2723–2731. 10.1038/jid.2015.277
    1. Ramesh G., MacLean A. G., Philipp M. T. (2013). Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm. 2013:480739. 10.1155/2013/480739
    1. Rathinam V. A., Jiang Z., Waggoner S. N., Sharma S., Cole L. E., Waggoner L., et al. . (2010). The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395–402. 10.1038/ni.1864
    1. Rathinam V. A., Vanaja S. K., Fitzgerald K. A. (2012). Regulation of inflammasome signaling. Nat. Immunol. 13, 333–342. 10.1038/ni.2237
    1. Redmond A. D. (1981). Dyskinesia induced by mefanimic acid? J. R. Soc. Med. 74, 558–559.
    1. Ribes S., Ebert S., Czesnik D., Regen T., Zeug A., Bukowski S., et al. . (2009). Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5alpha and Escherichia coli K1 strains by murine microglial cells. Infect. Immun. 77, 557–564. 10.1128/IAI.00903-08
    1. Rock R. B., Gekker G., Hu S., Sheng W. S., Cheeran M., Lokensgard J. R., et al. . (2004). Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17, 942–964. 10.1128/CMR.17.4.942-964.2004
    1. Roed C., Engsig F. N., Omland L. H., Skinhoj P., Obel N. (2012). Long-term mortality in patients diagnosed with Listeria monocytogenes meningitis: a Danish nationwide cohort study. J. Infect. 64, 34–40. 10.1016/j.jinf.2011.10.003
    1. Rosenzweig H. L., Planck S. R., Rosenbaum J. T. (2011). NLRs in immune privileged sites. Curr. Opin. Pharmacol. 11, 423–428. 10.1016/j.coph.2011.07.002
    1. Saijo K., Crotti A., Glass C. K. (2013). Regulation of microglia activation and deactivation by nuclear receptors. Glia 61, 104–111. 10.1002/glia.22423
    1. Saitoh T., Fujita N., Jang M. H., Uematsu S., Yang B. G., Satoh T., et al. . (2008). Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268. 10.1038/nature07383
    1. Saresella M., La Rosa F., Piancone F., Zoppis M., Marventano I., Calabrese E., et al. . (2016). The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol. Neurodegener. 11:23. 10.1186/s13024-016-0088-1
    1. Schmid-Burgk J. L., Chauhan D., Schmidt T., Ebert T. S., Reinhardt J., Endl E., et al. . (2016). A genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J. Biol. Chem. 291, 103–109. 10.1074/jbc.C115.700492
    1. Sehba F. A., Hou J., Pluta R. M., Zhang J. H. (2012). The importance of early brain injury after subarachnoid hemorrhage. Prog. Neurobiol. 97, 14–37. 10.1016/j.pneurobio.2012.02.003
    1. Shah V. B., Huang Y., Keshwara R., Ozment-Skelton T., Williams D. L., Keshvara L. (2008). β-glucan activates microglia without inducing cytokine production in Dectin-1-dependent manner. J. Immunol. 180, 2777–2785. 10.4049/jimmunol.180.5.2777
    1. Shao A., Wu H., Hong Y., Tu S., Sun X., Wu Q., et al. . (2016). Hydrogen-rich saline atenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: possible involvement of NF-κB pathway and NLRP3 inflammasome. Mol. Neurobiol. 53, 3462–3476. 10.1007/s12035-015-9242-y
    1. Sharp F. A., Ruane D., Claass B., Creagh E., Harris J., Malyala P., et al. . (2009). Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc. Natl. Acad. Sci. U S A 106, 870–875. 10.1073/pnas.0804897106
    1. Shi F., Kouadir M., Yang Y. (2015). NALP3 inflammasome activation in protein misfolding diseases. Life Sci. 135, 9–14. 10.1016/j.lfs.2015.05.011
    1. Shi C. S., Shenderov K., Huang N. N., Kabat J., Abu-Asab M., Fitzgerald K. A., et al. . (2012). Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263. 10.1038/ni.2215
    1. Shi H., Wang Y., Li X., Zhan X., Tang M., Fina M., et al. . (2016). NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258. 10.1038/ni.3333
    1. Shi F., Yang L., Kouadir M., Yang Y., Wang J., Zhou X., et al. . (2012). The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J. Neuroinflammation 9:73. 10.1186/1742-2094-9-73
    1. Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., et al. . (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665. 10.1038/nature15514
    1. Shi J. Q., Zhang C. C., Sun X. L., Cheng X. X., Wang J. B., Zhang Y. D., et al. . (2013). Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-κB and NLRP3 inflammasome activation. CNS Neurosci. Ther. 19, 262–268. 10.1016/j.jalz.2013.04.112
    1. Shrivastava S. K., Dalko E., Delcroix-Genete D., Herbert F., Cazenave P. A., Pied S. (2017). Uptake of parasite-derived vesicles by astrocytes and microglial phagocytosis of infected erythrocytes may drive neuroinflammation in cerebral malaria. Glia 65, 75–92. 10.1002/glia.23075
    1. Sifringer M., Stefovska V., Endesfelder S., Stahel P. F., Genz K., Dzietko M., et al. . (2007). Activation of caspase-1 dependent interleukins in developmental brain trauma. Neurobiol. Dis. 25, 614–622. 10.1016/j.nbd.2006.11.003
    1. Silver J., Miller J. H. (2004). Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156. 10.1038/nrn1326
    1. Silverman W. R., de Rivero Vaccari J. P., Locovei S., Qiu F., Carlsson S. K., Sceme S. E., et al. . (2009). The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J. Biol. Chem. 284, 18143–18151. 10.1074/jbc.m109.004804
    1. Sofroniew M. V. (2005). Reactive astrocytes in neural repair and protection. Neuroscientist 11, 400–407. 10.1177/1073858405278321
    1. Sofroniew M. V. (2009). Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647. 10.1016/j.tins.2009.08.002
    1. Sosunov A. A., Wu X., Tsankova N. M., Guilfoyle E., McKhann G. M., II., Goldman J. E. (2014). Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J. Neurosci. 34, 2285–2298. 10.1523/JNEUROSCI.4037-13.2014
    1. Srinivasula S. M., Poyet J. L., Razmara M., Datta P., Zhang Z., Alnemri E. S. (2002). The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122. 10.1074/jbc.c200179200
    1. Subramanian N., Natarajan K., Clatworthy M. R., Wang Z., Germain R. N. (2013). The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348–361. 10.1016/j.cell.2013.02.054
    1. Sutterwala F. S., Mijares L. A., Li L., Ogura Y., Kazmierczak B. I., Flavell R. A. (2007). Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. 204, 3235–3245. 10.1084/jem.20071239
    1. Sutterwala F. S., Ogura Y., Szczepanik M., Lara-Tejero M., Lichtenberger G. S., Grant E. P., et al. . (2006). Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327. 10.1016/j.immuni.2006.02.004
    1. Szretter K. J., Samuel M. A., Gilfillan S., Fuchs A., Colonna M., Diamond M. S. (2009). The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. J. Virol. 83, 9329–9338. 10.1128/JVI.00836-09
    1. Tahara K., Kim H. D., Jin J. J., Maxwell J. A., Li L., Fukuchi K. (2006). Role of toll-like receptor signalling in Aβ uptake and clearance. Brain 129, 3006–3019. 10.1093/brain/awl249
    1. Tang S. C., Wang Y. C., Li Y. I., Lin H. C., Manzanero S., Hsieh Y. H., et al. . (2013). Functional role of soluble receptor for advanced glycation end products in stroke. Arterioscler. Thromb. Vasc. Biol. 33, 585–594. 10.1161/ATVBAHA.112.300523
    1. Tan M. S., Tan L., Jiang T., Zhu X. C., Wang H. F., Jia C. D., et al. . (2014). Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease. Cell Death Dis. 5:e1382. 10.1038/cddis.2014.348
    1. Tan M. S., Yu J. T., Jiang T., Zhu X. C., Wang H. F., Zhang W., et al. . (2013). NLRP3 polymorphisms are associated with late-onset Alzheimer’s disease in Han Chinese. J. Neuroimmunol. 265, 91–95. 10.1016/j.jneuroim.2013.10.002
    1. Tate M. D., Ong J. D., Dowling J. K., McAuley J. L., Robertson A. B., Latz E., et al. . (2016). Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition. Sci. Rep. 6:27912. 10.1038/srep27912
    1. Thakkar R., Wang R., Sareddy G., Wang J., Thiruvaiyaru D., Vadlamudi R., et al. . (2016). NLRP3 inflammasome activation in the brain after global cerebral ischemia and regulation by 17β-estradiol. Oxid. Med. Cell. Longev. 2016:8309031. 10.1155/2016/8309031
    1. Thomas P. G., Dash P., Aldridge J. R., Jr., Ellebedy A. H., Reynolds C., Funk A. J., et al. . (2009). The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30, 566–575. 10.1016/j.immuni.2009.02.006
    1. Thønnings S., Knudsen J. D., Schønheyder H. C., Søgaard M., Arpi M., Gradel K. O., et al. . (2016). Antibiotic treatment and mortality in patients with Listeria monocytogenes meningitis or bacteraemia. Clin. Microbiol. Infect. 22, 725–730. 10.1016/j.cmi.2016.06.006
    1. Tixador P., Herzog L., Reine F., Jaumain E., Chapuis J., Le Dur A., et al. . (2010). The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog. 6:e1000859. 10.1371/journal.ppat.1000859
    1. Toldo S., Mezzaroma E., McGeough M. D., Peña C. A., Marchetti C., Sonnino C., et al. . (2015). Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart. Cardiovasc. Res. 105, 203–212. 10.1093/cvr/cvu259
    1. Tribouillard-Tanvier D., Striebel J. F., Peterson K. E., Chesebro B. (2009). Analysis of protein levels of 24 cytokines in scrapie agent-infected brain and glial cell cultures from mice differing in prion protein expression levels. J. Virol. 83, 11244–11253. 10.1128/JVI.01413-09
    1. Tsuda T., Munthasser S., Fraser P. E., Percy M. E., Rainero I., Vaula G., et al. . (1994). Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis. Neuron 13, 727–736. 10.1016/0896-6273(94)90039-6
    1. Walsh J. G., Reinke S. N., Mamik M. K., McKenzie B. A., Maingat F., Branton W. G., et al. . (2014). Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS. Retrovirology 11:35. 10.1186/1742-4690-11-35
    1. Wang J., Doré S. (2007). Inflammation after intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 27, 894–908. 10.1038/sj.jcbfm.9600403
    1. Wang X., Li R., Wang X., Fu Q., Ma S. (2015). Umbelliferone ameliorates cerebral ischemia–reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome. Neurosci. Lett. 600, 182–187. 10.1016/j.neulet.2015.06.016
    1. Warren S. E., Mao D. P., Rodriguez A. E., Miao E. A., Aderem A. (2008). Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J. Immunol. 180, 7558–7564. 10.4049/jimmunol.180.11.7558
    1. Werner C., Engelhard K. (2007). Pathophysiology of traumatic brain injury. Br. J. Anaesth. 99, 4–9. 10.1093/bja/aem131
    1. White C. S., Lawrence C. B., Brough D., Rivers-Auty J. (2017). Inflammmasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 27, 223–234. 10.1111/bpa.12478
    1. Willingham S. B., Bergstralh D. T., O’Connor W., Morrison A. C., Taxman D. J., Duncan J. A., et al. . (2007). Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2, 147–159. 10.1016/j.chom.2007.07.009
    1. Wilms H., Sievers J., Rickert U., Rostami-Yazdi M., Mrowietz U., Lucius R. (2010). Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation. J. Neuroinflammation 7:30. 10.1186/1742-2094-7-30
    1. Witiw C. D., Fehlings M. G. (2015). Acute spinal cord injury. J. Spinal Disord. Tech. 28, 202–210. 10.1097/BSD.0000000000000287
    1. Witten I. B., Steinberg E. E., Lee S. Y., Davidson T. J., Zalocusky K. A., Brodsky M., et al. . (2011). Recombinase-driver rat lines: tools, techniques and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733. 10.1016/j.neuron.2011.10.028
    1. Wu J., Fernandes-Alnemri T., Alnemri E. S. (2010). Involvement of the AIM2, NLRC4 and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J. Clin. Immunol. 30, 693–702. 10.1007/s10875-010-9425-2
    1. Xiao M., Li L., Li C., Liu L., Yu Y., Ma L. (2016). 3,4-methylenedioxy-β-nitrostyrene ameliorates experimental burn wound progression by inhibiting the NLRP3 inflammasome activation. Plast. Reconstr. Surg. 137, 566e–575e. 10.1097/01.prs.0000479972.06934.83
    1. Xian W., Wu Y., Xiong W., Li L., Li T., Pan S., et al. . (2016). The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response. Biochem. Biophys. Res. Commun. 472, 175–181. 10.1016/j.bbrc.2016.02.090
    1. Xie G., Tian W., Wei T., Liu F. (2015). The neuroprotective effects of β-hydroxybutyrate on Aβ-injected rat hippocampus in vivo and in Aβ-treated PC-12 cells in vitro. Free Radic. Res. 49, 139–150. 10.3109/10715762.2014.987274
    1. Xiong Y., Mahmood A., Chopp M. (2013). Animal models of traumatic brain injury. Nat. Rev. Neurosci. 14, 128–142. 10.1038/nrn3407
    1. Yang F., Wang Z., Wei X., Han H., Meng X., Zhang Y., et al. . (2014). NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J. Cereb. Blood Flow Metab. 34, 660–667. 10.1038/jcbfm.2013.242
    1. Yang Z., Zhong L., Xian R., Yuan B. (2015). MicroRNA-223 regulates inflammation and brain injury via feedback to NLRP3 inflammasome after intracerebral hemorrhage. Mol. Immunol. 65, 267–276. 10.1016/j.molimm.2014.12.018
    1. Yatsiv I., Morganti-Kossmann M. C., Perez D., Dinarello C. A., Novick D., Rubinstein M., et al. . (2002). Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury. J. Cereb. Blood Flow Metab. 22, 971–978. 10.1097/00004647-200208000-00008
    1. Yin Y., Yan Y., Jiang X., Mai J., Chen N. C., Wang H., et al. . (2009). Inflammasomes are differentially expressed in cardiovascular and other tissues. Int. J. Immunopathol. Pharmacol. 22, 311–322. 10.1177/039463200902200208
    1. Youm Y. H., Nguyen K. Y., Grant R. W., Goldberg E. L., Bodogai M., Kim D., et al. . (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269. 10.1038/nm.3804
    1. Yuan B., Shen H., Lin L., Su T., Zhong S., Yang Z. (2015). Recombinant adenovirus encoding NLRP3 RNAi attenuate inflammation and brain injury after intracerebral hemorrhage. J. Neuroinflammation 287, 71–75. 10.1016/j.jneuroim.2015.08.002
    1. Yu M., Zhang K., Qi W., Huang Z., Ye J., Ma Y., et al. . (2014). Expression pattern of NLRP3 and its related cytokines in the lung and brain of avian influenza virus H9N2 infected BALB/c mice. Virol. J. 11:229. 10.1186/s12985-014-0229-5
    1. Zendedel A., Johann S., Mehrabi S., Joghataei M., Hassanzadeh G., Kipp M., et al. . (2016). Activation and regulation of NLRP3 inflammasome by intrathecal application of SDF-1a in a spinal cord injury model. Mol. Neurobiol. 53, 3063–3075. 10.1007/s12035-015-9203-5
    1. Zhang Y., Barres B. A. (2010). Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594. 10.1016/j.conb.2010.06.005
    1. Zhang Q., Bian G., Chen P., Liu L., Yu C., Liu F., et al. . (2016). Aldose reductase regulates microglia/macrophages polarization through the cAMP response element-binding protein after spinal cord injury in mice. Mol. Neurobiol. 53, 662–676. 10.1007/s12035-014-9035-8
    1. Zhao W., Beers D. R., Bell S., Wang J., Wen S., Baloh R. H., et al. . (2015). TDP-43 activates microglia through NF-κB and NLRP3 inflammasome. Exp. Neurol. 273, 24–35. 10.1016/j.expneurol.2015.07.019
    1. Zhou R., Tardivel A., Thorens B., Choi I., Tschopp J. (2010). Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140. 10.1038/ni.1831
    1. Zhou R., Yazdi A. S., Menu P., Tschopp J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225. 10.1038/nature09663

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