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NLRP3 inflammasome: a promising target in ischemic stroke

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Abstract

Background

Recently, several studies have demonstrated that the NLRP3 inflammasome participates in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury following cerebral ischemia. More importantly, blocking or inhibiting NLRP3 inflammasome at multiple levels, such as its expression, assembly and activity, may offer substantial promise to salvage neurological deterioration during ischemic stroke. However, the specific mechanisms about the contribution of NLRP3 to neurovascular damage remain to be established.

Materials and methods

In this paper, we will review the molecular structure, expression and assembly of NLRP3 inflammasome, and illustrate its possible roles and effects in ischemic stroke. Moreover, we will speculate its activity and mechanism in stroke pathogenesis, and present the recent advances and challenges in potential therapies targeting NLRP3 inflammsome.

Results and conclusion

Mounting evidence has demonstrated that NLRP3 inflammasome plays a prominent role in the pathogenesis and progression of ischemic stroke, which indicates the higher possibility to target NLRP3 inflammasome in future stroke therapy. However, many aspects of the biology of NLRP3 inflammasome to stroke are still not well defined or even completely unknown. As the mechanistic insight of the NLRP3 inflammasomes increases, opportunities to develop new therapeutic strategies for patients with ischemic stroke are expected to enhance proportionately.

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References

  1. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 2012;32:1677–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fu Y, Liu Q, Anrather J, Shi FD. Immune interventions in stroke. Nat Rev Neurol. 2015;11:524–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. de Abulafia DP. Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab. 2009;29:534–44.

    Article  Google Scholar 

  4. Savage CD, Lopez-Castejon G, Denes A, Brough D. NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury. Front Immunol. 2012;3:288.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 2015;10:e0130624.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Deroide N, Li X, Lerouet D, Van Vré E, Baker L, Harrison J, Poittevin M, Masters L, Nih L, Margaill I, Iwakura Y, Ryffel B, Pocard M, Tedgui A, Kubis N, Mallat Z. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. J Clin Invest. 2013;123:1176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q, Yi F. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow. 2014;34:660–7.

    Article  CAS  Google Scholar 

  8. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    Article  CAS  PubMed  Google Scholar 

  9. de Zoete MR, Palm NW, Zhu S, Flavell RA. Inflammasomes. Cold Spring Harb Perspect Biol. 2014;6:a016287.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13:397–411.

    Article  CAS  PubMed  Google Scholar 

  11. Ye Z, Ting JP. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol. 2008;20:3–9.

    Article  CAS  PubMed  Google Scholar 

  12. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, Ting JP. Cryopyrin/NALP3 binds to ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci USA. 2007;104:8041–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, Hidaka E, Katsuyama T, Higuchi T, Sagara J. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem. 1999;274:33835–8.

    Article  CAS  PubMed  Google Scholar 

  14. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science. 1997;275:206–9.

    Article  CAS  PubMed  Google Scholar 

  15. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157:1013–22.

    Article  CAS  PubMed  Google Scholar 

  16. Cassel SL, Sutterwala FS. Sterile inflammatory responses mediated by the NLRP3 inflammasome. Eur J Immunol. 2010;40:607–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Legrand-Poels S, Esser N, L’homme L, Scheen A, Paquot N, Piette J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem Pharmacol. 2014;92:131–41.

    Article  CAS  PubMed  Google Scholar 

  20. Fann DY, Lee SY, Manzanero S, Chunduria P, Sobey CG, Arumugam TV. Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 2013;12:941–66.

    Article  CAS  PubMed  Google Scholar 

  21. Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ, Allan SM. Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab. 2012;32:1810–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Takahashi M. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013;99:4–5.

    Article  CAS  PubMed  Google Scholar 

  23. Liu SB, Mi WL, Wang YQ. Research progress on the NLRP3 inflammasome and its role in the central nervous system. Neurosci Bull. 2013;29:779–87.

    Article  PubMed  Google Scholar 

  24. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10:417–26.

    Article  CAS  PubMed  Google Scholar 

  25. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Núñe G, Inohara N. ASC is an activating adaptor for NF-κB and caspase-8-dependent apoptosis. Biochem Biophys Res Commun. 2003;303:69–73.

    Article  CAS  PubMed  Google Scholar 

  26. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem. 2002;277:21119–22.

    Article  CAS  PubMed  Google Scholar 

  27. Lamkanfi M, Dixit VM. Manipulation of host cell death pathways during microbial infections. Cell Host Microbe. 2010;8:44–54.

    Article  CAS  PubMed  Google Scholar 

  28. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Núñez G. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem. 2006;281:36560–8.

    Article  CAS  PubMed  Google Scholar 

  29. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galán JE, Askenase PW, Flavell RA. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 2006;24:317–27.

    Article  CAS  PubMed  Google Scholar 

  30. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.

    Article  CAS  PubMed  Google Scholar 

  31. Won JH, Park S, Hong S, Son S, Yu JW. Rotenone-induced Impairment of Mitochondrial Electron Transport Chain Confers a Selective Priming Signal for NLRP3 Inflammasome Activation. J Biol Chem. 2015;290:27425–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Petrilli 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;14:1583–9.

    Article  CAS  PubMed  Google Scholar 

  33. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. K + efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J. Syk kinase signaling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009;459:433–6.

    Article  CAS  PubMed  Google Scholar 

  36. Rajanbabu V, Galam L, Fukumoto J, Enciso J, Tadikonda P, Lane TN, Bandyopadhyay S, Parthasarathy PT, Cho Y, Cho SH, Lee YC, Lockey RF, Kolliputi N. Genipin suppresses NLRP3 inflammasome activation through uncoupling protein-2. Cell Immunol. 2015;297:40–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE. Mitochondria and reactive oxygen species. Free Radic Biol Med. 2009;47:333–43.

    Article  CAS  PubMed  Google Scholar 

  38. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem. 2014;289:9158–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shimada K, Crother TR, Karlin J, Dagvadori J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendori A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fann DY, Lee SY, Manzanero S, Gelderblom M, Chunduri P, Bernreuther C, Glatzel M, Cheng YL, Thundyil J, Widiapradja A, Lok KZ, Foo SL, Wang YC, Li YI, Drummond GR, Basta M, Magnus T, Jo DG, Mattson MP, Sobey CG, Arumugam TV. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4:e790.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang D, Yan H, Hu Y, Zhuang Z, Yu Z, Hang C. Increased expression of NLRP3 inflammasome in wall of ruptured and unruptured human cerebral aneurysms: preliminary results. J Stroke Cerebrovasc Dis. 2015;24:972–9.

    Article  PubMed  Google Scholar 

  43. Fann DY, Santro T, Manzanero S, Widiapradja A, Cheng YL, Lee SY, Chunduri P, Jo DG, Stranahan AM, Mattson MP, Arumugam TV. Intermittent fasting attenuates inflammasome activity in ischemic stroke. Exp Neurol. 2014;257:114–9.

    Article  CAS  PubMed  Google Scholar 

  44. Kastbom A, Ärlestig L, Rantapää-Dahlqvist S. Genetic variants of the NLRP3 inflammasome are associated with stroke in patients with rheumatoid arthritis. J Rheumatol. 2015;42:1740–5.

    Article  CAS  PubMed  Google Scholar 

  45. Denes A, Coutts G, Lénárt N, Cruickshank SM, Pelegrin P, Skinner J, Rothwell N, Allan SM, Brough D. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc Natl Acad Sci USA. 2015;112:4050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mongin AA. Disruption of ionic and cell volume homeostasis in cerebral ischemia: the perfect storm. Pathophysiology. 2007;14:183–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Soria FN, Perez-Samartin A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC, Matute C, Domercq M. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest. 2014;124:3645–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li Y, Li J, Li S, Wang X, Liu B, Fu Q, Ma S. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol Appl Pharmacol. 2015;286:53–63.

    Article  CAS  PubMed  Google Scholar 

  49. Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol. 2013;14:1247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, Walch E, Wirth T, O’Neill LA. Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem. 2003;278:26258–64.

    Article  CAS  PubMed  Google Scholar 

  51. Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, Morita R. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun. 2015;6:7360.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.

    Article  CAS  PubMed  Google Scholar 

  53. Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, Kornfeld H, Fitzgerald KA, Lavelle EC. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 2011;286:9587–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13:255–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12:222–3.

    Article  CAS  PubMed  Google Scholar 

  56. Yano T, Kurata S. Induction of autophagy via innate bacterial recognition. Autophagy. 2008;4:958–60.

    Article  CAS  PubMed  Google Scholar 

  57. Widiapradja A, Vegh V, Lok KZ, Manzanero S, Thundyil J, Gelderblom M, Cheng YL, Pavlovski D, Tang SC, Jo DG, Magnus T, Chan SL, Sobey CG, Reutens D, Basta M, Mattson MP, Arumugam TV. Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways. J Neurochem. 2012;122:321–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Herrera AF, Jacobsen ED. Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2014;20:5365–71.

    Article  CAS  PubMed  Google Scholar 

  59. Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A. Post-stroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology. 2015 (epub ahead of print).

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Authors and Affiliations

  1. Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201100, China

    Li Gao, Qing Dong, Zhenghong Song, Fei Shen & Yansheng Li

  2. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, China

    Jianquan Shi

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  1. Li Gao
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  2. Qing Dong
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Correspondence to Yansheng Li.

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Funding

This work was supported by Research Seed Training Program of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University (Grant No. RJZZ-14-018); Clinical Research Cultivation and Innovation Fund of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University (Grant No. PYZY16-004).

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All the authors declare that they have no competing interests.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Gao, L., Dong, Q., Song, Z. et al. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm. Res. 66, 17–24 (2017). https://doi.org/10.1007/s00011-016-0981-7

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