The NLRP3 Inflammasome: A Possible Therapeutic Target for Treatment of Stroke

  • Tauheed IshratEmail author
  • Sanaz Nasoohi
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Ischemic stroke is a complex systemic disease causing severe long-term disability and death worldwide. Experimental and clinical data have demonstrated that inflammation is a major component of ischemic stroke pathobiology. The post-ischemic neuroinflammatory response is characterized by microglial and astro-glial activation and increased expression of inflammatory mediators. Recent findings have provided insight into a newly discovered inflammatory mechanism that contributes to neuronal and glial cell death in neurodegenerative diseases and stroke mediated by inflammasomes. Interestingly, of inflammasomes described to date, NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) inflammasome is the best characterized multi-protein complexes and most strongly associated with sterile inflammation. In this chapter, we discuss in detail the prominent contribution and regulation of NLRP3-inflammasome activation in the pathophysiology of ischemic stroke. Furthermore, provide recent developments on the potential of NLRP3 inhibitors in the therapeutic management of stroke outcomes. The significant contribution of regulatory mechanisms of NLRP3 inflammasome with the development of stroke, may improve our understanding of NLRP3 inhibition for developing future therapies and novel drug targets for stroke.


NLRP3 Inflammasome Ischemic stroke Inflammation NOD-like receptor protein Neuronal death Inhibitors 


Amyloid beta


Adenosine di phosphate


Absence in melanoma


Age-related macular degeneration


AMP-activated protein kinase


Apoptosis-associated speck like


Apoptosis signal-regulating kinase


Acid-sensing ion channels


Adenosine di phosphate


Blood brain barrier


Brilliant blue G




BRCA1/BRCA2-containing complex, subunit 3


Bruton’s tyrosine kinase


Calcium sensing receptor


Cannabinoid receptor 2


C-type lectin receptor


Carbon monoxide




Central nervous system


Cytokine release inhibitory drugs


Chemokine (C-X-C motif) ligand-1


Damage-associated molecular patterns


Diphenylene iodonium


Deubiquitinating enzymes


Embolic middle cerebral artery occlusion


Experimental autoimmune encephalomyelitis


Epigallocatechin gallate


Prostaglandin E2 receptor 4


Endoplasmic reticulum stress


Free fatty acid


SCF complex subunit F-box L2


Glial fibrillary acidic protein


Glucose transporter-1


G protein-coupled receptor family C group 6 member A


Gasdermin D


Hydroxy-carboxylic acid receptor 2


Hypoxia inducible factor-1 alpha


Human retinal endothelial cells


Heat shock protein 90


Intracerebral hemorrhage




Interferon-alpha/beta receptor


Interleukin 1 beta


Inositol trisphosphate


Inositol-requiring 1


Inducible nitric oxide synthase


Interleukin-1 receptor-associated kinase 1


Janus kinase


c-jun-N-terminal kinase






Leucine rich repeat domain


Mitogen activated protein


Mitochondrial anti-viral signaling protein


Middle cerebral artery occlusion


Milk fat globule-EGF 8


Myocardial infarction


Mitogen-activated protein kinase


Micro ribonucleic acid


Mitochondrial Reactive oxygen species


Monocarboxylate transporter 1


Matrix metalloproteinase 9




Magnetic resonance imaging


Myeloid differentiation primary response 88


Nicotinamide adenine dinucleotide phosphate-oxidase


Nicotinamide adenine dinucleotide phosphate


Nicotinamide adenine dinucleotide phosphate


Nucleotide-binding domain


Nuclear factor kappa-B


Nucleotide-binding oligomerization domain like receptor


NOD-like receptor proteins




Nucleotide-binding oligomerization domain


Nicotinamide adenine dinucleotide phosphate oxidase


Oxygen glucose deprivation


Palmitate coupled to bovine serum albumin


Pathogen-associated molecular patterns


dsRNA-activated protein kinase-like ER kinase


Prostaglandin E2


Protein kinase A


Phospholipase c


Pyrophosphatase 2


Peroxisome proliferator-activated receptor-γ


Pattern recognition receptor


Phospho-tyrosine phosphatases


P2X purinoceptor 7


Raf-1 kinase inhibitory protein


Reactive oxygen species


Structure activity relationship




Suppressor of g2 allele of skp1


Solute carriers


SKP1-cullin-F-box protein


Sulfonylurea receptor 1


Signal transducers and activators of transcription


Transforming growth factor beta-activated kinase 1


Transient middle cerebral artery occlusion




Toll-like receptor


Tumor necrotizing factor α


TIR-domain-containing adapter-inducing interferon-β


Transient receptor potential melastatin 4




Thioredoxin interacting protein


Wild type



This chapter was supported by R01NS097800-01 to Tauheed Ishrat.

Disclosure of conflict of interest: None


  1. 1.
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Corbyn Z. A growing global burden. Nature. 2014;510(7506):S2.PubMedCrossRefGoogle Scholar
  3. 3.
    Barrington J, Lemarchand E, Allan SM. A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? Brain Pathol. 2017;27:205.PubMedCrossRefGoogle Scholar
  4. 4.
    Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17(7):796–808.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol. 2011;10(5):471–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe C-U, Siler DA, et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40(5):1849–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009;7(1):97.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Lénárt N, Brough D, Dénes Á. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab. 2016;36(10):1668–85.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Deroide N, Li X, Lerouet D, Van Vré E, Baker L, Harrison J, et al. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. J Clin Invest. 2013;123(3):1176–81.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 2014;34(4):660–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Luheshi NM, Kovács KJ, Lopez-Castejon G, Brough D, Denes A. Interleukin-1α expression precedes IL-1β after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues. J Neuroinflammation. 2011;8(1):186.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Vezzani A, Maroso M, Balosso S, Sanchez M-A, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun. 2011;25(7):1281–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.PubMedCrossRefGoogle Scholar
  15. 15.
    Cassel SL, Sutterwala FS. Sterile inflammatory responses mediated by the NLRP3 inflammasome. Eur J Immunol. 2010;40(3):607–11.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Suresh R, Mosser DM. Pattern recognition receptors in innate immunity, host defense, and immunopathology. Adv Physiol Educ. 2013;37(4):284–91.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol. 2011;29:707–35.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev. 2011;243(1):136–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsuchiya K, Hara H. The inflammasome and its regulation. Crit Rev Immunol. 2014;34(1):41–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.PubMedCrossRefGoogle Scholar
  21. 21.
    Man SM, Kanneganti TD. Regulation of inflammasome activation. Immunol Rev. 2015;265(1):6–21.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Próchnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016;5:F1000 Faculty Rev-1469.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481(7381):278–86.PubMedCrossRefGoogle Scholar
  24. 24.
    Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger? Science. 2010;327(5963):296–300.PubMedCrossRefGoogle Scholar
  25. 25.
    Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol. 2014;192(8):3881–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Embry CA, Franchi L, Nuñez G, Mitchell TC. Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci Signal. 2011;4(171):ra28.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–91.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287(43):36617–22.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Jin C, Flavell RA. Molecular mechanism of NLRP3 inflammasome activation. J Clin Immunol. 2010;30(5):628–31.PubMedCrossRefGoogle Scholar
  31. 31.
    Wen H, Miao EA, Ting JP-Y. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity. 2013;39(3):432–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature. 2011;474(7351):385–9.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gurung P, Malireddi RS, Anand PK, Demon D, Walle LV, Liu Z, et al. Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein-and Nlrp3 inflammasome-mediated host defense against enteropathogens. J Biol Chem. 2012;287(41):34474–83.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Aachoui Y, Sagulenko V, Miao EA, Stacey KJ. Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Curr Opin Microbiol. 2013;16(3):319–26.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature. 2012;490(7419):288–91.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell. 2012;150(3):606–19.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Schroder K, Sagulenko V, Zamoshnikova A, Richards AA, Cridland JA, Irvine KM, et al. Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction. Immunobiology. 2012;217(12):1325–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol. 2013;191(8):3995–9.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Py BF, Kim M-S, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2013;49(2):331–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Han S, Lear TB, Jerome JA, Rajbhandari S, Snavely CA, Gulick DL, et al. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase. J Biol Chem. 2015;290(29):18124–33.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015;160(1):62–73.PubMedCrossRefGoogle Scholar
  42. 42.
    Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun. 2015;6:7360.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Stutz A, Kolbe C-C, Stahl R, Horvath GL, Franklin BS, van Ray O, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med. 2017.; doi:jem. 20160933Google Scholar
  44. 44.
    Mariathasan S, Weiss DS, Newton K, McBride J, O’rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440(7081):228–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Compan V, Baroja-Mazo A, López-Castejón G, Gomez AI, Martínez CM, Angosto D, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012;37(3):487–500.PubMedCrossRefGoogle Scholar
  46. 46.
    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(6):1142–53.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Viganò E, Mortellaro A. Caspase-11: The driving factor for noncanonical inflammasomes. Eur J Immunol. 2013;43(9):2240–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Walev I, Reske K, Palmer M, Valeva A, Bhakdi S. Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J. 1995;14(8):1607.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Perregaux D, Barberia J, Lanzetti AJ, Geoghegan KF, Carty T, Gabel C. IL-1 beta maturation: evidence that mature cytokine formation can be induced specifically by nigericin. J Immunol. 1992;149(4):1294–303.PubMedGoogle Scholar
  50. 50.
    He Y, Zeng MY, Yang D, Motro B, Núñez G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 2016;530:354.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Shi H, Wang Y, Li X, Zhan X, Tang M, Fina M, et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol. 2016;17:250.PubMedCrossRefGoogle Scholar
  52. 52.
    Bartlett R, Stokes L, Sluyter R. The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol Rev. 2014;66(3):638–75.PubMedCrossRefGoogle Scholar
  53. 53.
    Kelkar DA, Chattopadhyay A. The gramicidin ion channel: a model membrane protein. Biochim Biophys Acta. 2007;1768(9):2011–25.PubMedCrossRefGoogle Scholar
  54. 54.
    Pressman BC. Biological applications of ionophores. Annu Rev Biochem. 1976;45(1):501–30.PubMedCrossRefGoogle Scholar
  55. 55.
    Clapham DE. Calcium signaling. Cell. 1995;80(2):259–68.PubMedCrossRefGoogle Scholar
  56. 56.
    Walsh C, Barrow S, Voronina S, Chvanov M, Petersen OH, Tepikin A. Modulation of calcium signalling by mitochondria. Biochim Biophys Acta. 2009;1787(11):1374–82.PubMedCrossRefGoogle Scholar
  57. 57.
    Duchen MR. Mitochondria and calcium: from cell signalling to cell death. J Physiol. 2000;529(1):57–68.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Okada M, Matsuzawa A, Yoshimura A, Ichijo H. The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. J Biol Chem. 2014;289(47):32926–36.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yaron J, Gangaraju S, Rao M, Kong X, Zhang L, Su F, et al. K+ regulates Ca2+ to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis. 2015;6(10):e1954.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Brough D, Le Feuvre RA, Wheeler RD, Solovyova N, Hilfiker S, Rothwell NJ, et al. Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1β and IL-1α from murine macrophages. J Immunol. 2003;170(6):3029–36.PubMedCrossRefGoogle Scholar
  61. 61.
    Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci. 2012;109(28):11282–7.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K. 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins (1, 4, 5) P3-induced Ca2+ release. The. J Biochem. 1997;122(3):498–505.PubMedCrossRefGoogle Scholar
  63. 63.
    Bleasdale JE, Thakur NR, Gremban RS, Bundy GL, Fitzpatrick FA, Smith RJ, et al. Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils. J Pharmacol Exp Ther. 1990;255(2):756–68.PubMedGoogle Scholar
  64. 64.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9(8):847–56.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453(7198):1122–6.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hentze H, Lin X, Choi M, Porter A. Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin. Cell Death Differ. 2003;10(9):956–68.PubMedCrossRefGoogle Scholar
  67. 67.
    Deng D, Jiang N, Hao S-J, Sun H, G-j Z. Loss of membrane cholesterol influences lysosomal permeability to potassium ions and protons. Biochim Biophys Acta. 2009;1788(2):470–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Lima H Jr, Jacobson L, Goldberg M, Chandran K, Diaz-Griffero F, Lisanti MP, et al. Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle. 2013;12(12):1868–78.PubMedCrossRefGoogle Scholar
  69. 69.
    Martinon F. Signaling by ROS drives inflammasome activation. Eur J Immunol. 2010;40(3):616–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell. 2013;153(2):348–61.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol. 2013;191(8):4358–66.PubMedCrossRefGoogle Scholar
  73. 73.
    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40.PubMedCrossRefGoogle Scholar
  74. 74.
    Wang W, Wang C, Ding XQ, Pan Y, TT G, Wang MX, et al. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol. 2013;169(6):1352–71.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    El-Azab M, Baldowski B, Mysona B, Shanab A, Mohamed I, Abdelsaid M, et al. Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury. Br J Pharmacol. 2014;171(5):1299–313.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Mohamed IN, Hafez SS, Fairaq A, Ergul A, Imig JD, El-Remessy AB. Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia. 2014;57(2):413–23.PubMedCrossRefGoogle Scholar
  77. 77.
    Chen J, Cha-Molstad H, Szabo A, Shalev A. Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein. Am J Physiol Endocrinol Metab. 2009;296(5):E1133–E9.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1 [beta] in type 2 diabetes. Nat Immunol. 2010;11(10):897–904.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Meyer Y, Buchanan BB, Vignols F, Reichheld J-P. Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu Rev Genet. 2009;43:335–67.PubMedCrossRefGoogle Scholar
  80. 80.
    Patwari P, Higgins LJ, Chutkow WA, Yoshioka J, Lee RT. The interaction of thioredoxin with Txnip evidence for formation of a mixed disulfide by disulfide exchange. J Biol Chem. 2006;281(31):21884–91.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Singh LP. Thioredoxin interacting protein (TXNIP) and pathogenesis of diabetic retinopathy. J Clin Exp Ophthalmol. 2013;4Google Scholar
  82. 82.
    Pejnovic NN, Pantic JM, Jovanovic IP, Radosavljevic GD, Milovanovic MZ, Nikolic IG, et al. Galectin-3 deficiency accelerates high-fat diet–induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. Diabetes. 2013;62(6):1932–44.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Chung JW, JH JEON, SR YOON, Choi I. Vitamin D3 upregulated protein 1 (VDUP1) is a regulator for redox signaling and stress-mediated diseases. J Dermatol. 2006;33(10):662–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol. 2000;164(12):6287–95.PubMedCrossRefGoogle Scholar
  85. 85.
    Polekhina G, Ascher DB, Kok SF, Waltham M. Crystallization and preliminary X-ray analysis of the N-terminal domain of human thioredoxin-interacting protein. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011;67(5):613–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Spindel ON, Berk BC. Thioredoxin-Interacting Protein Mediates TRX1 Translocation to the Plasma Membrane in Response to Tumor Necrosis Factor-α. Arterioscler Thromb Vasc Biol. 2011;31(8):1890–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Saxena G, Chen J, Shalev A. Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem. 2010;285(6):3997–4005.PubMedCrossRefGoogle Scholar
  88. 88.
    Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013;49(6):1167–75.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ding C, Zhao Y, Shi X, Zhang N, Zu G, Li Z, et al. New insights into salvianolic acid A action: regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats. Sci Rep. 2016;6:28734.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Chen W, Zhao M, Zhao S, Lu Q, Ni L, Zou C, et al. Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline. Inflamm Res. 2017;66:157–66.PubMedCrossRefGoogle Scholar
  91. 91.
    Ye X, Zuo D, Yu L, Zhang L, Tang J, Cui C, et al. ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia. Biochem Biophys Res Commun. 2017;485(2):499–505.PubMedCrossRefGoogle Scholar
  92. 92.
    Lv H, Liu Q, Wen Z, Feng H, Deng X, Ci X. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol. 2017;12:311–24.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yin Y, Zhou Z, Liu W, Chang Q, Sun G, Dai Y. Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway. Int J Biochem Cell Biol. 2017;84:22.PubMedCrossRefGoogle Scholar
  94. 94.
    Gao P, He F-F, Tang H, Lei C-T, Chen S, Meng X-F, et al. NADPH oxidase-induced NALP3 inflammasome activation is driven by thioredoxin-interacting protein which contributes to podocyte injury in hyperglycemia. J Diabetes Res. 2015;2015:504761.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Liu W, Gu J, Qi J, Zeng XN, Ji J, Chen ZZ, et al. Lentinan exerts synergistic apoptotic effects with paclitaxel in A549 cells via activating ROS-TXNIP-NLRP3 inflammasome. J Cell Mol Med. 2015;19(8):1949–55.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Xiao J, Liu Y, Xing F, Leung TM, Liong EC, Tipoe GL. Bee’s honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein–NLRP3 inflammasome pathway. Eur J Nutr. 2016;55(4):1465–77.PubMedCrossRefGoogle Scholar
  97. 97.
    Feng H, Gu J, Gou F, Huang W, Gao C, Chen G, et al. High glucose and lipopolysaccharide prime NLRP3 inflammasome via ROS/TXNIP pathway in mesangial cells. J Diabet Res. 2016;2016:6973175.Google Scholar
  98. 98.
    Jiang L, Fei D, Gong R, Yang W, Yu W, Pan S, et al. CORM-2 inhibits TXNIP/NLRP3 inflammasome pathway in LPS-induced acute lung injury. Inflamm Res. 2016;65(11):905–15.PubMedCrossRefGoogle Scholar
  99. 99.
    Dinesh P, Rasool M. Berberine, an isoquinoline alkaloid suppresses TXNIP mediated NLRP3 inflammasome activation in MSU crystal stimulated RAW 264.7 macrophages through the upregulation of Nrf2 transcription factor and alleviates MSU crystal induced inflammation in rats. Int Immunopharmacol. 2017;44:26–37.PubMedCrossRefGoogle Scholar
  100. 100.
    Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Choe J-Y, Kim S-K. Quercetin and ascorbic acid suppress fructose-induced NLRP3 inflammasome activation by blocking intracellular shuttling of TXNIP in human macrophage cell lines. Inflammation. 2017;40:980–94.PubMedCrossRefGoogle Scholar
  102. 102.
    Tan CY, Weier Q, Zhang Y, Cox AJ, Kelly DJ, Langham RG. Thioredoxin-interacting protein: a potential therapeutic target for treatment of progressive fibrosis in diabetic nephropathy. Nephron. 2015;129(2):109–27.PubMedCrossRefGoogle Scholar
  103. 103.
    Zhang X, Zhang J-H, Chen X-Y, Q-H H, Wang M-X, Jin R, et al. Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation. Antioxid Redox Signal. 2015;22(10):848–70.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Wang W, Wu Q-h, Sui Y, Wang Y, Qiu X. Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome. Biomed Pharmacother. 2017;86:32–40.PubMedCrossRefGoogle Scholar
  105. 105.
    Zhang Q-Y, Pan Y, Wang R, Kang L-L, Xue Q-C, Wang X-N, et al. Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats. J Nutr Biochem. 2014;25(4):420–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Hu Q, Wei B, Wei L, Hua K, Yu X, Li H, et al. Sodium tanshinone IIA sulfonate ameliorates ischemia-induced myocardial inflammation and lipid accumulation in Beagle dogs through NLRP3 inflammasome. Int J Cardiol. 2015;196:183–92.PubMedCrossRefGoogle Scholar
  107. 107.
    Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M, et al. Ruscogenin attenuates cerebral ischemia-induced blood-brain barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int J Mol Sci. 2016;17(9):1418.PubMedCentralCrossRefGoogle Scholar
  108. 108.
    Wang X, Li R, Wang X, Fu Q, Ma S. Umbelliferone ameliorates cerebral ischemia–reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome. Neurosci Lett. 2015;600:182–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Li Y, Li J, Li S, Li Y, Wang X, Liu B, et al. 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(1):53–63.PubMedCrossRefGoogle Scholar
  110. 110.
    Ishrat T, Mohamed IN, Pillai B, Soliman S, Fouda AY, Ergul A, et al. Thioredoxin-interacting protein: a novel target for neuroprotection in experimental thromboembolic stroke in mice. Mol Neurobiol. 2015;51(2):766–78.PubMedCrossRefGoogle Scholar
  111. 111.
    Saitoh T, Akira S. Regulation of inflammasomes by autophagy. J Allergy Clin Immunol. 2016;138(1):28–36.PubMedCrossRefGoogle Scholar
  112. 112.
    Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, et al. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J Biol Chem. 2011;286(11):9587–97.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Nakahira K, Haspel JA, Rathinam VA, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.PubMedCrossRefGoogle Scholar
  114. 114.
    Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol. 2013;14(5):480–8.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Smoum R, Baraghithy S, Chourasia M, Breuer A, Mussai N, Attar-Namdar M, et al. CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse relationship between binding affinity and biological potency. Proc Natl Acad Sci. 2015;112(28):8774–9.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Shao BZ, Wei W, Ke P, ZQ X, Zhou JX, Liu C. Activating cannabinoid receptor 2 alleviates pathogenesis of experimental autoimmune encephalomyelitis via activation of autophagy and inhibiting NLRP3 inflammasome. CNS Neurosci Ther. 2014;20(12):1021–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Lee G-S, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012;492(7427):123–7.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. 2013;38(6):1154–63.PubMedCrossRefGoogle Scholar
  119. 119.
    Desouza IA, CF F-P, Camargo EA, Lima CS, Teixeira SA, Muscará MN, et al. Inflammatory mechanisms underlying the rat pulmonary neutrophil influx induced by airway exposure to staphylococcal enterotoxin type A. Br J Pharmacol. 2005;146(6):781–91.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Tajima T, Murata T, Aritake K, Urade Y, Hirai H, Nakamura M, et al. Lipopolysaccharide induces macrophage migration via prostaglandin D2 and prostaglandin E2. J Pharmacol Exp Ther. 2008;326(2):493–501.PubMedCrossRefGoogle Scholar
  121. 121.
    Kvirkvelia N, McMenamin M, Chaudhary K, Bartoli M, Madaio MP. Prostaglandin E2 promotes cellular recovery from established nephrotoxic serum nephritis in mice, prosurvival, and regenerative effects on glomerular cells. Am J Physiol Renal Physiol. 2013;304(5):F463–F70.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    MacKenzie KF, Clark K, Naqvi S, McGuire VA, Nöehren G, Kristariyanto Y, et al. PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A–SIK–CRTC3 pathway. J Immunol. 2013;190(2):565–77.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Sokolowska M, Chen L-Y, Liu Y, Martinez-Anton A, Qi H-Y, Logun C, et al. Prostaglandin E2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cyclic AMP in human macrophages. J Immunol. 2015;194(11):5472–87.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Mortimer L, Moreau F, MacDonald JA, Chadee K. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat Immunol. 2017;17:1176.CrossRefGoogle Scholar
  125. 125.
    Swanson KV, Ting JP. Reining in uncontrolled inflammasome with PKA. Nat Immunol. 2016;17(10):1137–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Chen S, Sun B. Negative regulation of NLRP3 inflammasome signaling. Protein Cell. 2013;4(4):251.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey A-A, Pich D, McInnes IB, et al. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production. J Immunol. 2012;189(8):3795–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Bauernfeind F, Rieger A, Schildberg FA, Knolle PA, Schmid-Burgk JL, Hornung V. NLRP3 inflammasome activity is negatively controlled by miR-223. J Immunol. 2012;189(8):4175–81.PubMedCrossRefGoogle Scholar
  129. 129.
    Li X-F, Shen W-W, Sun Y-Y, Li W-X, Sun Z-H, Liu Y-H, et al. MicroRNA-20a negatively regulates expression of NLRP3-inflammasome by targeting TXNIP in adjuvant-induced arthritis fibroblast-like synoviocytes. Joint Bone Spine. 2016;83(6):695–700.PubMedCrossRefGoogle Scholar
  130. 130.
    Bandyopadhyay S, Lane T, Venugopal R, Parthasarathy PT, Cho Y, Galam L, et al. MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2. Biochem Biophys Res Commun. 2013;439(3):407–12.PubMedCrossRefGoogle Scholar
  131. 131.
    Wang W, Ding X-Q, T-T G, Song L, Li J-M, Xue Q-C, et al. Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. Free Radic Biol Med. 2015;83:214–26.PubMedCrossRefGoogle Scholar
  132. 132.
    Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature. 2006;442(7098):39–44.PubMedCrossRefGoogle Scholar
  133. 133.
    Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, et al. IFNβ therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci Signal. 2011;5(225):ra38.Google Scholar
  134. 134.
    Inoue M, Shinohara ML. The role of interferon-β in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis–in the perspective of inflammasomes. Immunology. 2013;139(1):11–8.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Förster I, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34(2):213–23.PubMedCrossRefGoogle Scholar
  136. 136.
    Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, et al. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 2015;10(6):e0130624.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Abulafia DP, de 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(3):534–44.PubMedCrossRefGoogle Scholar
  138. 138.
    Fann DY-W, Lee S, Manzanero S, Tang S-C, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4(9):e790.PubMedCrossRefGoogle Scholar
  139. 139.
    Afrasyab A, Qu P, Zhao Y, Peng K, Wang H, Lou D, et al. Correlation of NLRP3 with severity and prognosis of coronary atherosclerosis in acute coronary syndrome patients. Heart Vessels. 2016;31(8):1218–29.PubMedCrossRefGoogle Scholar
  140. 140.
    Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol. 2008;9(8):857–65.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A. Poststroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology. 2016;103(5):460–75.PubMedCrossRefGoogle Scholar
  142. 142.
    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(5):972–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Abdul-Muneer P, Alikunju S, Mishra V, Schuetz H, Szlachetka AM, Burnham EL, et al. Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions. Brain Behav Immun 2017: 62: 291.Google Scholar
  144. 144.
    Soria FN, Pérez-Samartín A, Martin A, Gona KB, Llop J, Szczupak B, et al. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest. 2014;124(8):3645–55.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Fann DY-W, Lee S-Y, Manzanero S, Chunduri P, Sobey CG, Arumugam TV. Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 2013;12(4):941–66.PubMedCrossRefGoogle Scholar
  146. 146.
    Han S, Kim K, Kim H, Kwon J, Lee Y-H, Lee C-K, et al. Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE 2 production in macrophages. Arch Pharm Res. 2008;31(1):67–74.PubMedCrossRefGoogle Scholar
  147. 147.
    Yamada R, Sano H, Hla T, Hashiramoto A, Fukui W, Miyazaki S, et al. Auranofin inhibits interleukin-1β-induced transcript of cyclooxygenase-2 on cultured human synoviocytes. Eur J Pharmacol. 1999;385(1):71–9.PubMedCrossRefGoogle Scholar
  148. 148.
    Cox AG, Brown KK, Arner ES, Hampton MB. The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol. 2008;76(9):1097–109.PubMedCrossRefGoogle Scholar
  149. 149.
    Jeon K-I, Jeong J-Y, Jue D-M. Thiol-reactive metal compounds inhibit NF-κB activation by blocking IκB kinase. J Immunol. 2000;164(11):5981–9.PubMedCrossRefGoogle Scholar
  150. 150.
    Kataoka K, Handa H, Nishizawa M. Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold (I) compounds. J Biol Chem. 2001;276(36):34074–81.PubMedCrossRefGoogle Scholar
  151. 151.
    Youn HS, Lee JY, Saitoh SI, Miyake K, Hwang DH. Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem Biophys Res Commun. 2006;350(4):866–71.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Sha T, Sunamoto M, Kitazaki T, Sato J, Ii M, Iizawa Y. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol. 2007;571(2):231–9.PubMedCrossRefGoogle Scholar
  153. 153.
    Zhang D, Yan H, Li H, Hao S, Zhuang Z, Liu M, et al. TGFβ-activated kinase 1 (TAK1) inhibition by 5Z-7-oxozeaenol attenuates early brain injury after experimental subarachnoid hemorrhage. J Biol Chem. 2015;290(32):19900–9.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Chang CA, Kanak MA, Yoshimatsu G, Lawrence MC, Kane RR, Naziruddin B. A small molecule inhibitor of toll-like receptor-4 (tlr-4) effectively protects islets from Ibmir. Xenotransplantation. 2015;22:S156.Google Scholar
  155. 155.
    Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157(7):1250–62.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    de Seny D, Cobraiville G, Charlier E, Neuville S, Esser N, Malaise D, et al. Acute-phase serum amyloid a in osteoarthritis: regulatory mechanism and proinflammatory properties. PLoS One. 2013;8(6):e66769.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Glushkova OV, Parfenyuk SB, Khrenov MO, Novoselova TV, Lunin SM, Fesenko EE, et al. Inhibitors of TLR-4, NF-κ B, and SAPK/JNK signaling reduce the toxic effect of lipopolysaccharide on RAW 264.7 cells. J Immunotoxicol. 2013;10(2):133–40.PubMedCrossRefGoogle Scholar
  158. 158.
    Gong Y-N, Wang X, Wang J, Yang Z, Li S, Yang J, et al. Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Res. 2010;20(12):1289–305.PubMedCrossRefGoogle Scholar
  159. 159.
    Hua F, Tang H, Wang J, Prunty MC, Hua X, Sayeed I, et al. TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice. J Cereb Blood Flow Metab. 2015;35(4):536–42.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    White BJ, Tarabishy S, Venna VR, Manwani B, Benashski S, McCullough LD, et al. Protection from cerebral ischemia by inhibition of TGFβ-activated kinase. Exp Neurol. 2012;237(1):238–45.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Gong J, Li Z-Z, Guo S, Zhang X-J, Zhang P, Zhao G-N, et al. Neuron-specific tumor necrosis factor receptor–associated factor 3 is a central regulator of neuronal death in acute ischemic strokenovelty and significance. Hypertension. 2015;66(3):604–16.PubMedCrossRefGoogle Scholar
  162. 162.
    Lopez-Castejon G, Luheshi NM, Compan V, High S, Whitehead RC, Flitsch S, et al. Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome. J Biol Chem. 2013;288(4):2721–33.PubMedCrossRefGoogle Scholar
  163. 163.
    Doeppner TR, Doehring M, Bretschneider E, Zechariah A, Kaltwasser B, Müller B, et al. MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation. Acta Neuropathol. 2013;126(2):251–65.PubMedCrossRefGoogle Scholar
  164. 164.
    Min JW, Lü L, Freeling J, Martin D, Wang H. USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice. J Neurochem. 2017;140:826.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, J-W Y, et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem. 2010;285(13):9792–802.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Saadane A, Masters S, DiDonato J, Li J, Berger M. Parthenolide inhibits IκB kinase, NF-κB activation, and inflammatory response in cystic fibrosis cells and mice. Am J Respir Cell Mol Biol. 2007;36(6):728–36.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Garcı́a-Piñeres AJ, Vc C, Mora G, Schmidt TJ, Strunck E, Pahl HL, et al. Cysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem. 2001;276(43):39713–20.PubMedCrossRefGoogle Scholar
  168. 168.
    Meng X, Martinez MA, MA R-S, Winter SS, Wilson BS. IKK inhibitor bay 11-7082 induces necroptotic cell death in precursor-B acute lymphoblastic leukaemic blasts. Br J Haematol. 2010;148(3):487–90.PubMedCrossRefGoogle Scholar
  169. 169.
    Dong L, Qiao H, Zhang X, Zhang X, Wang C, Wang L, et al. Parthenolide is neuroprotective in rat experimental stroke model: downregulating NF-B, phospho-p38MAPK, and caspase-1 and ameliorating BBB permeability. Mediators Inflamm. 2013;2013:370804.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. 2007;110(13):4427–35.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    D’anneo A, Carlisi D, Lauricella M, Puleio R, Martinez R, Di Bella S, et al. Parthenolide generates reactive oxygen species and autophagy in MDA-MB231 cells. A soluble parthenolide analogue inhibits tumour growth and metastasis in a xenograft model of breast cancer. Cell Death Dis. 2013;4(10):e891.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Su L, Du H, Dong X, Zhang X, Lou Z. Raf kinase inhibitor protein regulates oxygen-glucose deprivation-induced PC12 cells apoptosis through the NF-κB and ERK pathways. J Clin Biochem Nutr. 2016;59(2):86–92.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Su L, Zhang R, Chen Y, Ma C, Zhu Z. Raf kinase inhibitor protein attenuates ischemic-induced microglia cell apoptosis and activation through NF-κB pathway. Cell Physiol Biochem. 2017;41(3):1125–34.PubMedCrossRefGoogle Scholar
  174. 174.
    He Y, Varadarajan S, Muñoz-Planillo R, Burberry A, Nakamura Y, Núñez G. 3, 4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem. 2014;289(2):1142–50.PubMedCrossRefGoogle Scholar
  175. 175.
    Xiao M, Li L, Li C, Liu L, Yu Y, Ma L. 3, 4-methylenedioxy-β-nitrostyrene ameliorates experimental burn wound progression by inhibiting the NLRP3 inflammasome activation. Plast Reconstr Surg. 2016;137(3):566e–75e.PubMedCrossRefGoogle Scholar
  176. 176.
    Long H, Xu B, Luo Y, Luo K. Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation. Am J Emerg Med. 2016;34(5):772–7.PubMedCrossRefGoogle Scholar
  177. 177.
    Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB, Team DS. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Annal Rheum Dis. 2012;71:1630.CrossRefGoogle Scholar
  178. 178.
    Stock TC, Bloom BJ, Wei N, Ishaq S, Park W, Wang X, et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol. 2012;39(4):720–7.PubMedCrossRefGoogle Scholar
  179. 179.
    Ali Z, Laurijssens B, Ostenfeld T, McHugh S, Stylianou A, Scott-Stevens P, et al. Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects. Br J Clin Pharmacol. 2013;75(1):197–207.PubMedCrossRefGoogle Scholar
  180. 180.
    Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, et al. The P2X7 receptor: a key player in IL-1 processing and release. J Immunol. 2006;176(7):3877–83.PubMedCrossRefGoogle Scholar
  181. 181.
    Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med. 2012;18(4):595–9.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Ferrari D, Chiozzi P, Falzoni S, Dal Susino M, Melchiorri L, Baricordi OR, et al. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol. 1997;159(3):1451–8.PubMedGoogle Scholar
  183. 183.
    Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, et al. Altered cytokine production in mice lacking P2X7Receptors. J Biol Chem. 2001;276(1):125–32.PubMedCrossRefGoogle Scholar
  184. 184.
    Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, et al. Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol. 2002;168(12):6436–45.PubMedCrossRefGoogle Scholar
  185. 185.
    Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 2006;25(21):5071–82.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Locovei S, Scemes E, Qiu F, Spray DC, Dahl G. Pannexin1 is part of the pore forming unit of the P2X 7 receptor death complex. FEBS Lett. 2007;581(3):483–8.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Kanneganti T-D, Lamkanfi M, Kim Y-G, Chen G, Park J-H, Franchi L, et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity. 2007;26(4):433–43.PubMedCrossRefGoogle Scholar
  188. 188.
    Bravo D, Maturana C, Pelissier T, Hernández A, Constandil L. Interactions of pannexin 1 with NMDA and P2X7 receptors in central nervous system pathologies: possible role on chronic pain. Pharmacol Res. 2015;101:86–93.PubMedCrossRefGoogle Scholar
  189. 189.
    Brough D, Le Feuvre RA, Iwakura Y, Rothwell NJ. Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism. Mol Cell Neurosci. 2002;19(2):272–80.PubMedCrossRefGoogle Scholar
  190. 190.
    Arbeloa J, Pérez-Samartín A, Gottlieb M, Matute C. P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemia. Neurobiol Dis. 2012;45(3):954–61.PubMedCrossRefGoogle Scholar
  191. 191.
    Eyo UB, Miner SA, Ahlers KE, L-J W, Dailey ME. P2X7 receptor activation regulates microglial cell death during oxygen-glucose deprivation. Neuropharmacology. 2013;73:311–9.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Zhao H, Zhang X, Dai Z, Feng Y, Li Q, Zhang JH, et al. P2X7 receptor suppression preserves blood-brain barrier through inhibiting RhoA activation after experimental intracerebral hemorrhage in rats. Sci Rep. 2016;6:23286.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Ye X, Shen T, Hu J, Zhang L, Zhang Y, Bao L, et al. Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse. Exp Neurol. 2017;292:46–55.PubMedCrossRefGoogle Scholar
  194. 194.
    Lu M, Yang J-Z, Geng F, Ding J-H, Hu G. Iptakalim confers an antidepressant effect in a chronic mild stress model of depression through regulating neuro-inflammation and neurogenesis. Int J Neuropsychopharmacol. 2014;17(9):1501–10.PubMedCrossRefGoogle Scholar
  195. 195.
    Zhao AP, Dong YF, Liu W, Gu J, Sun XL. Nicorandil inhibits inflammasome activation and toll-like receptor-4 signal transduction to protect against oxygen–glucose deprivation-induced inflammation in BV-2 cells. CNS Neurosci Ther. 2014;20(2):147–53.PubMedCrossRefGoogle Scholar
  196. 196.
    Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol. 2013;191(10):5230–8.PubMedCrossRefGoogle Scholar
  197. 197.
    Biswas R, Hamilton RF, Holian A. Role of lysosomes in silica-induced inflammasome activation and inflammation in absence of MARCO. J Immunol Res. 2014;2014:304180.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Morishige T, Yoshioka Y, Tanabe A, Yao X, Tsunoda S-i, Tsutsumi Y, et al. Titanium dioxide induces different levels of IL-1β production dependent on its particle characteristics through caspase-1 activation mediated by reactive oxygen species and cathepsin B. Biochem Biophys Res Commun. 2010;392(2):160–5.PubMedCrossRefGoogle Scholar
  199. 199.
    Bruchard M, Mignot G, Derangère V, Chalmin F, Chevriaux A, Végran F, et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. 2013;19(1):57–64.PubMedCrossRefGoogle Scholar
  200. 200.
    Jacobson LS, Lima H, Goldberg MF, Gocheva V, Tsiperson V, Sutterwala FS, et al. Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. J Biol Chem. 2013;288(11):7481–91.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Montaser M, Lalmanach G, Mach L. CA-074, but not its methyl ester CA-074Me, is a selective inhibitor of cathepsin B within living cells. Biol Chem. 2002;383(7-8):1305–8.PubMedCrossRefGoogle Scholar
  202. 202.
    Chen YT, Brinen LS, Kerr ID, Hansell E, Doyle PS, McKerrow JH, et al. In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. PLoS Negl Trop Dis. 2010;4(9):e825.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Orlowski GM, Colbert JD, Sharma S, Bogyo M, Robertson SA, Rock KL. Multiple cathepsins promote pro–IL-1β synthesis and NLRP3-mediated IL-1β activation. J Immunol. 2015;195(4):1685–97.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Hou Q, Ling L, Wang F, Xing S, Pei Z, Zeng J. Endostatin expression in neurons during the early stage of cerebral ischemia is associated with neuronal apoptotic cell death in adult hypertensive rat model of stroke. Brain Res. 2010;1311:182–8.PubMedCrossRefGoogle Scholar
  205. 205.
    Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem. 2007;282(5):2871–9.PubMedCrossRefGoogle Scholar
  206. 206.
    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(9):1583–9.PubMedCrossRefGoogle Scholar
  207. 207.
    Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674–7.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13(6):397–411.PubMedCrossRefGoogle Scholar
  209. 209.
    Álvarez S, Muñoz-Fernández MÁ. TNF-α may mediate inflammasome activation in the absence of bacterial infection in more than one way. PLoS One. 2013;8(8):e71477.PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT-H, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–15.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Xiao H, Lu M, Lin TY, Chen Z, Chen G, Wang W-C, et al. SREBP2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility. Circulation. 2013;128:632.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Sreerama L, Sladek NE. Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. Biochem Pharmacol. 1993;45(12):2487–505.PubMedCrossRefGoogle Scholar
  213. 213.
    Laliberte RE, Perregaux DG, Hoth LR, Rosner PJ, Jordan CK, Peese KM, et al. Glutathione S-transferase omega 1-1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1β posttranslational processing. J Biol Chem. 2003;278(19):16567–78.PubMedCrossRefGoogle Scholar
  214. 214.
    Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–55.PubMedPubMedCentralGoogle Scholar
  215. 215.
    Sušjan P, Roškar S, Hafner-Bratkovič I. The mechanism of NLRP3 inflammasome initiation: trimerization but not dimerization of the NLRP3 pyrin domain induces robust activation of IL-1β. Biochem Biophys Res Commun. 2017;483:823.PubMedCrossRefGoogle Scholar
  216. 216.
    Salla M, Butler MS, Pelingon R, Kaeslin G, Croker DE, Reid JC, et al. Identification, synthesis, and biological evaluation of the major human metabolite of NLRP3 inflammasome inhibitor MCC950. ACS Med Chem Lett. 2016;7(12):1034–8.PubMedCrossRefGoogle Scholar
  217. 217.
    Dempsey C, Araiz AR, Bryson K, Finucane O, Larkin C, Mills E, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017;61:306–16.PubMedCrossRefGoogle Scholar
  218. 218.
    Dolunay A, Senol SP, Temiz-Resitoglu M, Guden DS, Sari AN, Sahan-Firat S, et al. Inhibition of NLRP3 inflammasome prevents LPS-induced inflammatory hyperalgesia in mice: contribution of NF-κB, caspase-1/11, ASC, NOX, and NOS isoforms. Inflammation. 2017;40:366–86.PubMedCrossRefGoogle Scholar
  219. 219.
    Takahashi M. NLRP3 inflammasome as a novel player in myocardial infarction. Int Heart J. 2014;55(2):101–5.PubMedCrossRefGoogle Scholar
  220. 220.
    van Hout GP, Bosch L, Ellenbroek GH, de Haan JJ, van Solinge WW, Cooper MA, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2017;38:828.PubMedGoogle Scholar
  221. 221.
    Mohamed IN, Ishrat T, Fagan SC, El-Remessy AB. Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit. Antioxid Redox Signal. 2015;22(13):1188–206.PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Murthy P, Durco F, Miller-Ocuin JL, Takedai T, Shankar S, Liang X, et al. The NLRP3 inflammasome and bruton’s tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation. Biochem Biophys Res Commun. 2017;483(1):230–6.PubMedCrossRefGoogle Scholar
  223. 223.
    Mercken EM, Crosby SD, Lamming DW, JeBailey L, Krzysik-Walker S, Villareal DT, et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell. 2013;12(4):645–51.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52.PubMedCrossRefGoogle Scholar
  225. 225.
    Netea MG, Joosten LA. Inflammasome inhibition: putting out the fire. Cell Metab. 2015;21(4):513–4.PubMedCrossRefGoogle Scholar
  226. 226.
    Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9.PubMedPubMedCentralGoogle Scholar
  227. 227.
    Bae HR, Kim DH, Park MH, Lee B, Kim MJ, Lee EK, et al. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016;7(41):66444–54.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304(8):H1060–H76.PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Halestrap AP. Monocarboxylic acid transport. Compr Physiol. 2013;3:1611.PubMedCrossRefGoogle Scholar
  230. 230.
    Bergersen LH, Magistretti PJ, Pellerin L. Selective postsynaptic co-localization of MCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA receptor trafficking. Cereb Cortex. 2005;15(4):361–70.PubMedCrossRefGoogle Scholar
  231. 231.
    Edmond J, Robbins R, Bergstrom J, Cole R, De Vellis J. Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J Neurosci Res. 1987;18(4):551–61.PubMedCrossRefGoogle Scholar
  232. 232.
    Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149.PubMedPubMedCentralGoogle Scholar
  233. 233.
    Pikija S, Trkulja V, Simundic A-M, Vrcek E, Boskovic K, Bacani S. Is on-admission capillary blood beta-hydroxybutyrate concentration associated with the acute stroke severity and short-term functional outcome? Neurol Res. 2013;35(9):959–67.PubMedCrossRefGoogle Scholar
  234. 234.
    Puchowicz MA, Zechel JL, Valerio J, Emancipator DS, Xu K, Pundik S, et al. Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab. 2008;28(12):1907–16.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, et al. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun. 2014;5:3944.PubMedCrossRefGoogle Scholar
  236. 236.
    Offermanns S, Schwaninger M. Nutritional or pharmacological activation of HCA 2 ameliorates neuroinflammation. Trends Mol Med. 2015;21(4):245–55.PubMedCrossRefGoogle Scholar
  237. 237.
    Kinard TA, Satin LS. An ATP-sensitive Cl− channel current that is activated by cell swelling, cAMP, and glyburide in insulin-secreting cells. Diabetes. 1995;44(12):1461–6.PubMedCrossRefGoogle Scholar
  238. 238.
    Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest. 2005;115(8):2047–58.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Watanabe T, Takeda A, Tsukiyama T, Mise K, Okuno T, Sasaki H, et al. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 2006;20(13):1732–43.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Perregaux DG, McNiff P, Laliberte R, Hawryluk N, Peurano H, Stam E, et al. Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors. J Pharmacol Exp Ther. 2001;299(1):187–97.PubMedGoogle Scholar
  241. 241.
    Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol. 2009;187(1):61–70.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Coll RC, O’Neill LA. The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS One. 2011;6(12):e29539.PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Sturgess N, Cook D, Ashford MJ, Hales CN. The sulphonylurea receptor may be an ATP-sensitive potassium channel. Lancet. 1985;326(8453):474–5.CrossRefGoogle Scholar
  244. 244.
    Henquin J-C. Tolbutamide stimulation and inhibition of insulin release: studies of the underlying ionic mechanisms in isolated rat islets. Diabetologia. 1980;18(2):151–60.PubMedCrossRefGoogle Scholar
  245. 245.
    Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, et al. Human monocytes engage an alternative inflammasome pathway. Immunity. 2016;44(4):833–46.PubMedCrossRefGoogle Scholar
  246. 246.
    Liu W, Guo W, Wu J, Luo Q, Tao F, Gu Y, et al. A novel benzo [d] imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome. Biochem Pharmacol. 2013;85(10):1504–12.PubMedCrossRefGoogle Scholar
  247. 247.
    Pan L, Hang N, Zhang C, Chen Y, Li S, Sun Y, et al. Synthesis and biological evaluation of novel benzimidazole derivatives and analogs targeting the NLRP3 inflammasome. Molecules. 2017;22(2):213.CrossRefGoogle Scholar
  248. 248.
    Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev. 1998;56(11):317–33.PubMedCrossRefGoogle Scholar
  249. 249.
    Cerella C, Radogna F, Dicato M, Diederich M. Natural compounds as regulators of the cancer cell metabolism. Int J Cell Biol. 2013;2013:639401.PubMedPubMedCentralGoogle Scholar
  250. 250.
    Huang T-T, Lai H-C, Chen Y-B, Chen L-G, Y-H W, Ko Y-F, et al. cis-Resveratrol produces anti-inflammatory effects by inhibiting canonical and non-canonical inflammasomes in macrophages. Innate Immun. 2014;20(7):735–50.PubMedCrossRefGoogle Scholar
  251. 251.
    Chang YP, Ka SM, Hsu WH, Chen A, Chao LK, Lin CC, et al. Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy. J Cell Physiol. 2015;230(7):1567–79.PubMedCrossRefGoogle Scholar
  252. 252.
    Wu J, Li X, Zhu G, Zhang Y, He M, Zhang J. The role of resveratrol-induced mitophagy/autophagy in peritoneal mesothelial cells inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS. Exp Cell Res. 2016;341(1):42–53.PubMedCrossRefGoogle Scholar
  253. 253.
    Barrajón-Catalán E, Herranz-López M, Joven J, Segura-Carretero A, Alonso-Villaverde C, Menéndez JA, et al. Molecular promiscuity of plant polyphenols in the management of age-related diseases: far beyond their antioxidant properties. In: Oxidative stress and inflammation in non-communicable diseases-molecular mechanisms and perspectives in therapeutics. New York, NY: Springer; 2014. p. 141–59.Google Scholar
  254. 254.
    Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493–506.PubMedCrossRefGoogle Scholar
  255. 255.
    Sharma R, Gescher A, Steward W. Curcumin: the story so far. Eur J Cancer. 2005;41(13):1955–68.PubMedCrossRefGoogle Scholar
  256. 256.
    Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008;133(3):387–91.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Hooper PL, Hooper PL, Tytell M, Vígh L. Xenohormesis: health benefits from an eon of plant stress response evolution. Cell Stress Chaperones. 2010;15(6):761–70.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Queen BL, Tollefsbol TO. Polyphenols and aging. Curr Aging Sci. 2010;3(1):34–42.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Hua F, Tang H, Wang J, Prunty MC, Hua X, Sayeed I, et al. TAK-242, an antagonist for toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice. J Cereb Blood Flow Metab. 2015;1:7.Google Scholar
  260. 260.
    Fann D, Lim Y, Cheng Y, Lok K, Chunduri P, Baik S, et al. Evidence that NF-κB and MAPK signaling promotes NLRP inflammasome activation in neurons following ischemic stroke. Mol Neurobiol. 2017;Google Scholar
  261. 261.
    Jian Z, Ding S, Deng H, Wang J, Yi W, Wang L, et al. Probenecid protects against oxygen–glucose deprivation injury in primary astrocytes by regulating inflammasome activity. Brain Res. 2016;1643:123–9.PubMedCrossRefGoogle Scholar
  262. 262.
    Qin Y-Y, Li M, Feng X, Wang J, Cao L, Shen X-K, et al. Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke. Free Radic Biol Med. 2017;104:333–45.PubMedCrossRefGoogle Scholar
  263. 263.
    He Y-B, Nan L-H, Huang M, Zheng Y-F, Yang L, Xu W, et al. Paeoniflorin down-regulates the expression of NLRP1 and NLRP3 inflammasomes in rat hippocampal slices after oxygen-glucose deprivation. Int J Clin Exp Med. 2016;9(6):10907–14.Google Scholar
  264. 264.
    Qiu J, Wang M, Zhang J, Cai Q, Lu D, Li Y, et al. The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. Int Immunopharmacol. 2016;40:492–500.PubMedCrossRefGoogle Scholar
  265. 265.
    Zhang N, Zhang X, Liu X, Wang H, Xue J, Yu J, et al. Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice. Mediators Inflamm. 2014;2014:370530.PubMedPubMedCentralGoogle Scholar
  266. 266.
    Kono S, Kurata T, Sato K, Omote Y, Hishikawa N, Yamashita T, et al. Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24(3):537–47.PubMedCrossRefGoogle Scholar
  267. 267.
    Lu Y, Xiao G, Luo W. Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke. Neuroimmunomodulation. 2016;23(4):230–8.PubMedCrossRefGoogle Scholar
  268. 268.
    Cheng Y, Wei Y, Yang W, Song Y, Shang H, Cai Y, et al. Cordycepin confers neuroprotection in mice models of intracerebral hemorrhage via suppressing NLRP3 inflammasome activation. Metab Brain Dis. 2017;32:1133–45.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Anatomy and Neurobiology, College of MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran

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