Inflammasomes link vascular disease with neuroinflammation and brain disorders

Journal of Cerebral Blood Flow and Metabolism

Volumn 36, Issue 10, 2016, Pages 1668-1685

  Lénárt, Nikolett ^a   Brough, David ^b   Dénes, Ádám ^a  

^a INSTITUTE OF EXPERIMENTAL MEDICINE   (Hungary)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

brain disease; inflammasome; Inflammation; neurodegeneration; systemic

Indexed keywords

AIM2 PROTEIN; CRYOPYRIN; INFLAMMASOME; INTERLEUKIN 1; INTERLEUKIN 18; NLRC4 PROTEIN; UNCLASSIFIED DRUG; CYTOKINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; NONSTEROID ANTIINFLAMMATORY AGENT;

ALZHEIMER DISEASE; ASTROCYTE; ATHEROSCLEROSIS; BRAIN DISEASE; BRAIN INJURY; CELL METABOLISM; CEREBROVASCULAR DISEASE; COMORBIDITY; DEMENTIA; DIABETES MELLITUS; DISEASE ASSOCIATION; EPILEPSY; GRANULOCYTE; HUMAN; HYPERTENSION; INFECTION; MENTAL DISEASE; MIGRAINE; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; OBESITY; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; STIMULUS RESPONSE; TISSUE INJURY; TRAUMATIC BRAIN INJURY; VASCULAR DISEASE; ANIMAL; BRAIN DISEASES; DRUG EFFECTS; IMMUNOLOGY; METABOLISM; NEUROGENIC INFLAMMATION; PATHOLOGY; VASCULAR DISEASES;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; BRAIN DISEASES; CYTOKINES; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; INFLAMMASOMES; NEUROGENIC INFLAMMATION; VASCULAR DISEASES;

EID: 84989859508     PISSN: 0271678X     EISSN: 15597016     Source Type: Journal    
DOI: 10.1177/0271678X16662043     Document Type: Review

References (221)

1. Yu M, Wang H, Ding A, et al. HMGB1 signals through toll-like receptor (TLR) 4, and TLR2. Shock 2006; 26: 174-179
2. Lu YC, Yeh WC, and Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42: 145-151
3. Newton K, and Dixit VM. Signaling in innate immunity, and inflammation. Cold Spring Harb Perspect Biol 2012; 4(3): pii: a006049
4. Serhan CN, and Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6: 1191-1197
5. Umegaki H. Neurodegeneration in diabetes mellitus. Adv Exp Med Biol 2012; 724: 258-265
6. Cai H, Cong WN, Ji S, et al. Metabolic dysfunction in Alzheimer's disease, and related neurodegenerative disorders. Curr Alzheimer Res 2012; 9: 5-17
7. Perry VH, Cunningham C, and Holmes C. Systemic infections, and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007; 7: 161-167
8. Murray KN, Buggey HF, Denes A, et al. Systemic immune activation shapes stroke outcome. Mol Cell Neurosci 2013; 53: 14-25
9. Smith CJ, Lawrence CB, Rodriguez-Grande B, et al. The immune system in stroke: clinical challenges, and their translation to experimental research. J Neuroimmune Pharmacol 2013; 8: 867-887
10. Drake C, Boutin H, Jones MS, et al. Brain inflammation is induced by co-morbidities, and risk factors for stroke. Brain Behav Immun 2011; 25: 1113-1122
11. Denes A, Drake C, Stordy J, et al. Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis. J Am Heart Assoc 2012; 1: e002006
12. Codolo G, Plotegher N, Pozzobon T, et al. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 2013; 8: e55375
13. Salminen A, Ojala J, Kauppinen A, et al. Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 2009; 87: 181-194
14. Wes PD, Easton A, Corradi J, et al. Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease. PLoS One 2014; 9: e106050
15. Rodrigues RJ, Tome AR, and Cunha RA. ATP as a multi-target danger signal in the brain. Front Neurosci 2015; 9: 148
16. Rock KL, and Kono H. The inflammatory response to cell death. Annu Rev Pathol 2008; 3: 99-126
17. Brough D, and Denes A. Interleukin-1alpha, and brain inflammation. IUBMB Life 2015; 67: 323-330
18. Lleo A, Galea E, and Sastre M. Molecular targets of nonsteroidal anti-inflammatory drugs in neurodegenerative diseases. Cell Mol Life Sci 2007; 64: 1403-1418
19. Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 2005; 18: 315-321
20. Denes A, Thornton P, Rothwell NJ, et al. Inflammation, and brain injury: acute cerebral ischaemia, peripheral, and central inflammation. Brain Behav Immun 2010; 24: 708-723
21. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015; 14: 388-405
22. Najjar S, Pearlman DM, Alper K, et al. Neuroinflammation, and psychiatric illness. J Neuroinflammation 2013; 10: 43
23. Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7: 31-40
24. Waeber C, and Moskowitz MA. Migraine as an inflammatory disorder. Neurology 2005; 64: S9-S15
25. Schiess M. Nonsteroidal anti-inflammatory drugs protect against Parkinson neurodegeneration: can an NSAID a day keep Parkinson disease away? Arch Neurol 2003; 60: 1043-1044
26. Dinarello CA. Interleukin-1 in the pathogenesis, and treatment of inflammatory diseases. Blood 2011; 117: 3720-3732
27. Murray KN, Parry-Jones AR, and Allan SM. Interleukin-1, and acute brain injury. Front Cell Neurosci 2015; 9: 18
28. Denes A, Pinteaux E, Rothwell NJ, et al. Interleukin-1, and stroke: biomarker, harbinger of damage, and therapeutic target. Cerebrovasc Dis 2011; 32: 517-527
29. Gracie JA, Robertson SE, and McInnes IB. Interleukin-18. J Leukoc Biol 2003; 73: 213-224
30. Alboni S, Cervia D, Sugama S, et al. Interleukin 18 in the CNS. J Neuroinflammation 2010; 7: 9
31. Ojala J, Alafuzoff I, Herukka SK, et al. Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients. Neurobiol Aging 2009; 30: 198-209
32. Dinarello CA. Interleukin 1, and interleukin 18 as mediators of inflammation, and the aging process. Am J Clin Nutr 2006; 83: 447S-455S
33. Guo H, Callaway JB, and Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677-687
34. de Rivero Vaccari JP, Lotocki G, Alonso OF, et al. Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response, and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 2009; 29: 1251-1261
35. Abulafia DP, de Rivero Vaccari JP, Lozano JD, et al. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 2009; 29: 534-544
36. de Rivero Vaccari JP, Lotocki G, Marcillo AE, et al. A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci 2008; 28: 3404-3414
37. Fann DY, Lee SY, Manzanero S, et al. Intravenous immunoglobulin suppresses NLRP1, and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis 2013; 4: e790
38. Ito M, Shichita T, Okada M, et al. Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation, and contributes to ischaemic brain injury. Nat Commun 2015; 6: 7360
39. Yang F, Wang Z, Wei X, et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab 2014; 34: 660-667
40. Denes A, Coutts G, Lenart N, et al. AIM2, and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc Natl Acad Sci USA 2015; 112: 4050-4055
41. Adamczak SE, de Rivero Vaccari JP, Dale G, et al. Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J Cereb Blood Flow Metab 2014; 34: 621-629
42. Kofoed EM, and Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 2011; 477: 592-595
43. Wen H, Miao EA, and Ting JP. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 2013; 39: 432-441
44. Fernandes-Alnemri T, Yu JW, Datta P, et al. AIM2 activates the inflammasome, and cell death in response to cytoplasmic DNA. Nature 2009; 458: 509-513
45. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA, and forms a caspase-1-activating inflammasome with ASC. Nature 2009; 458: 514-518
46. Cai X, Chen J, Xu H, et al. Prion-like polymerization underlies signal transduction in antiviral immune defense, and inflammasome activation. Cell 2014; 156: 1207-1222
47. Lu A, Magupalli VG, Ruan J, et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 2014; 156: 1193-1206
48. Lopez-Castejon G, and Brough D. Understanding the mechanism of IL-1beta secretion. Cytokine Growth Factor Rev 2011; 22: 189-195
49. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 2014; 15: 738-748
50. Franklin BS, Bossaller L, De Nardo D, et al. The adaptor ASC has extracellular, and ?prionoid? activities that propagate inflammation. Nat Immunol 2014; 15: 727-737
51. Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015; 526: 666-671
52. Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015; 526: 660-665
53. He WT, Wan H, Hu L, et al. Gasdermin D is an executor of pyroptosis, and required for interleukin-1beta secretion. Cell Res 2015; 25: 1285-1298
54. Martin-Sanchez F, Diamond C, Zeitler M, et al. Inflammasome-dependent IL-1beta release depends upon membrane permeabilisation. Cell Death Differ 2016; 23: 1219-1231
55. Yaidikar L, Byna B, and Thakur SR. Neuroprotective effect of punicalagin against cerebral ischemia reperfusion-induced oxidative brain injury in rats. J Stroke Cerebrovasc Dis 2014; 23: 2869-2878
56. Yaidikar L, and Thakur S. Punicalagin attenuated cerebral ischemia-reperfusion insult via inhibition of proinflammatory cytokines, up-regulation of Bcl-2, down-regulation of Bax, and caspase-3. Mol Cell Biochem 2015; 402: 141-148
57. Forlenza OV, Diniz BS, Talib LL, et al. Increased serum IL-1beta level in Alzheimer's disease, and mild cognitive impairment. Dement Geriatr Cogn Disord 2009; 28: 507-512
58. Ravaglia G, Paola F, Maioli F, et al. Interleukin-1beta, and interleukin-6 gene polymorphisms as risk factors for AD: a prospective study. Exp Gerontol 2006; 41: 85-92
59. Zhu Z, Yan J, Geng C, et al. A polymorphism within the 3?UTR of NLRP3 is associated with susceptibility for ischemic stroke in Chinese population. Cell Mol Neurobiol 2015; 36: 981-988
60. Arman A, Isik N, Coker A, et al. Association between sporadic Parkinson disease, and interleukin-1 beta -511 gene polymorphisms in the Turkish population. Eur Cytokine Netw 2010; 21: 116-121
61. Schuh E, Lohse P, Ertl-Wagner B, et al. Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations. Neurol Neuroimmunol Neuroinflamm 2015; 2: e109
62. Alcocer-Gomez E, and Cordero MD. NLRP3 inflammasome: a new target in major depressive disorder. CNS Neurosci Ther 2014; 20: 294-295
63. McGeer PL, Yasojima K, and McGeer EG. Association of interleukin-1 beta polymorphisms with idiopathic Parkinson's disease. Neurosci Lett 2002; 326: 67-69
64. Kunnas T, Maatta K, and Nikkari ST. NLR family pyrin domain containing 3 (NLRP3) inflammasome gene polymorphism rs7512998 (C>T) predicts aging-related increase of blood pressure, the TAMRISK study. Immun Ageing 2015; 12: 19
65. Klen J, Goricar K, Janez A, et al. NLRP3 inflammasome polymorphism, and macrovascular complications in type 2 diabetes patients. J Diabetes Res 2015; 2015: 616747
66. Omi T, Kumada M, Kamesaki T, et al. An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression, and is associated with essential hypertension. Eur J Hum Genet 2006; 14: 1295-1305
67. Varghese GP, Uporova L, Halfvarson J, et al. Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene, and inflammatory bowel disease. Mol Med Rep 2015; 11: 4579-4584
68. Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer's disease, and contributes to pathology in APP/PS1 mice. Nature 2013; 493: 674-678
69. Gris D, Ye Z, Iocca HA, et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1, and Th17 responses. J Immunol 2010; 185: 974-981
70. Inoue M, Williams KL, Gunn MD, et al. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2012; 109: 10480-10485
71. Jha S, Srivastava SY, Brickey WJ, et al. The inflammasome sensor, NLRP3, regulates CNS inflammation, and demyelination via caspase-1, and interleukin-18. J Neurosci 2010; 30: 15811-15820
72. Shi F, Yang L, Kouadir M, et al. The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J Neuroinflammation 2012; 9: 73
73. Meissner F, Molawi K, and Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA 2010; 107: 13046-13050
74. Lamkanfi M, and Dixit VM. Inflammasomes, and their roles in health, and disease. Annu Rev Cell Dev Biol 2012; 28: 137-161
75. Lamkanfi M, and Dixit VM. Mechanisms, and functions of inflammasomes. Cell 2014; 157: 1013-1022
76. Weber MD, Frank MG, Tracey KJ, et al. Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia, and the NLRP3 inflammasome. J Neurosci 2015; 35: 316-324
77. Savage CD, Lopez-Castejon G, Denes A, et al. 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
78. Gustin A, Kirchmeyer M, Koncina E, et al. NLRP3 inflammasome is expressed, and functional in mouse brain microglia but not in astrocytes. PLoS One 2015; 10: e0130624
79. Burm SM, Zuiderwijk-Sick EA, t Jong AE, et al. Inflammasome-induced IL-1beta secretion in microglia is characterized by delayed kinetics, and is only partially dependent on inflammatory caspases. J Neurosci 2015; 35: 678-687
80. Halle A, Hornung V, Petzold GC, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 2008; 9: 857-865
81. Freeman D, Cedillos R, Choyke S, et al. Alpha-synuclein induces lysosomal rupture, and cathepsin dependent reactive oxygen species following endocytosis. PLoS One 2013; 8: e62143
82. Gustot A, Gallea JI, Sarroukh R, et al. Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease. Biochem J 2015; 471: 323-333
83. Hafner-Bratkovic I, Bencina M, Fitzgerald KA, et al. NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta, and neuronal toxicity. Cell Mol Life Sci 2012; 69: 4215-4228
84. Ramaswamy V, Walsh JG, Sinclair DB, et al. Inflammasome induction in Rasmussen's encephalitis: cortical, and associated white matter pathogenesis. J Neuroinflammation 2013; 10: 152
85. Kaushal V, Dye R, Pakavathkumar P, et al. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production, and axonal degeneration-associated Caspase-6 activation. Cell Death Differ 2015; 22: 1676-1686
86. Bergsbaken T, Fink SL, and Cookson BT. Pyroptosis: host cell death, and inflammation. Nat Rev Microbiol 2009; 7: 99-109
87. Tan MS, Tan L, Jiang T, et al. Amyloid-beta induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell Death Dis 2014; 5: e1382
88. Tan CC, Zhang JG, Tan MS, et al. NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy, and contributes to neuronal pyroptosis in amygdala kindling-induced rat model. J Neuroinflammation 2015; 12: 18
89. Meng XF, Wang XL, Tian XJ, et al. Nod-like receptor protein 1 inflammasome mediates neuron injury under high glucose. Mol Neurobiol 2014; 49: 673-684
90. Johann S, Heitzer M, Kanagaratnam M, et al. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS, and in human sporadic ALS patients. Glia 2015; 63: 2260-2273
91. Lau LT, and Yu AC. Astrocytes produce, and release interleukin-1, interleukin-6, tumor necrosis factor alpha, and interferon-gamma following traumatic, and metabolic injury. J Neurotrauma 2001; 18: 351-359
92. Zeis T, Allaman I, Gentner M, et al. Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling. Brain Behav Immun 2015; 48: 313-325
93. Minkiewicz J, de Rivero Vaccari JP, and Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia 2013; 61: 1113-1121
94. Silverman WR, de Rivero Vaccari JP, Locovei S, et al. The pannexin 1 channel activates the inflammasome in neurons, and astrocytes. J Biol Chem 2009; 284: 18143-18151
95. Lu M, Sun XL, Qiao C, et al. Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress, and nod-like receptor protein 3 inflammasome activation. Neurobiol Aging 2014; 35: 421-430
96. Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, et al. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation, and cell death in astroglial cells. Front Cell Neurosci 2014; 8: 216
97. Zou J, and Crews FT. Inflammasome-IL-1beta signaling mediates ethanol inhibition of hippocampal neurogenesis. Front Neurosci 2012; 6: 77
98. Liu L, and Chan C. IPAF inflammasome is involved in interleukin-1beta production from astrocytes, induced by palmitate; implications for Alzheimer's Disease. Neurobiol Aging 2014; 35: 309-321
99. Nagyoszi P, Nyul-Toth A, Fazakas C, et al. Regulation of NOD-like receptors, and inflammasome activation in cerebral endothelial cells. J Neurochem 2015; 135: 551-564
100. Chen Z, Wen L, Martin M, et al. Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a. Circulation 2015; 131: 805-814
101. Zhang Y, Li X, Pitzer AL, et al. Coronary endothelial dysfunction induced by nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: beyond inflammation. Antioxid Redox Signal 2015; 22: 1084-1096
102. Xia M, Boini KM, Abais JM, et al. Endothelial NLRP3 inflammasome activation, and enhanced neointima formation in mice by adipokine visfatin. Am J Pathol 2014; 184: 1617-1628
103. Martin-Rodriguez S, Caballo C, Gutierrez G, et al. TLR4, and NALP3 inflammasome in the development of endothelial dysfunction in uraemia. Eur J Clin Invest 2015; 45: 160-169
104. Mohamed IN, Hafez SS, Fairaq A, et al. Thioredoxininteracting protein is required for endothelial NLRP3 inflammasome activation, and cell death in a rat model of high-fat diet. Diabetologia 2014; 57: 413-423
105. Bleda S, de Haro J, Varela C, et al. NLRP1 inflammasome, and not NLRP3, is the key in the shift to proinflammatory state on endothelial cells in peripheral arterial disease. Int J Cardiol 2014; 172: e282-e284
106. Kahlenberg JM, Thacker SG, Berthier CC, et al. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol 2011; 187: 6143-6156
107. Xiang M, Shi X, Li Y, et al. Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells. J Immunol 2011; 187: 4809-4817
108. Khakpour S, Wilhelmsen K, and Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun 2015; 21: 827-846
109. Curtiss LK, and Tobias PS. Emerging role of Toll-like receptors in atherosclerosis. J Lipid Res 2009; 50 Suppl: S340-S345
110. Pandey S, and Agrawal DK. Immunobiology of Toll-like receptors: emerging trends. Immunol Cell Biol 2006; 84: 333-341
111. Miranda-Hernandez S, and Baxter AG. Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol 2013; 2: 75-93
112. Kolaczkowska E, and Kubes P. Neutrophil recruitment, and function in health, and inflammation. Nat Rev Immunol 2013; 13: 159-175
113. Allen C, Thornton P, Denes A, et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J Immunol 2012; 189: 381-392
114. Giles JA, Greenhalgh AD, Davies CL, et al. Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity. Eur J Immunol 2015; 45: 525-530
115. Bakele M, Joos M, Burdi S, et al. Localization, and functionality of the inflammasome in neutrophils. J Biol Chem 2014; 289: 5320-5329
116. Chen KW, Gross CJ, Sotomayor FV, et al. The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge. Cell Rep 2014; 8: 570-582
117. Karmakar M, Katsnelson M, Malak HA, et al. Neutrophil IL-1beta processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome, and caspase-1 activation, and is dependent on K+ efflux. J Immunol 2015; 194: 1763-1775
118. Simpson JL, Phipps S, Baines KJ, et al. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J 2014; 43: 1067-1076
119. Migita K, Izumi Y, Jiuchi Y, et al. Serum amyloid A induces NLRP-3-mediated IL-1beta secretion in neutrophils. PLoS One 2014; 9: e96703
120. Lindemann S, Tolley ND, Dixon DA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490
121. Ahmad R, Iannello A, Samarani S, et al. Contribution of platelet activation to plasma IL-18 concentrations in HIV-infected AIDS patients. AIDS 2006; 20: 1907-1909
122. Thornton P, McColl BW, Greenhalgh A, et al. Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 2010; 115: 3632-3639
123. Morrell CN, Aggrey AA, Chapman LM, et al. Emerging roles for platelets as immune, and inflammatory cells. Blood 2014; 123: 2759-2767
124. Kleinschnitz C, Pozgajova M, Pham M, et al. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 2007; 115: 2323-2330
125. Denes A, Pradillo JM, Drake C, et al. Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1, and platelet glycoprotein Ibalpha. Ann Neurol 2014; 75: 670-683
126. Hottz ED, Lopes JF, Freitas C, et al. Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood 2013; 122: 3405-3414
127. Hottz ED, Monteiro AP, Bozza FA, et al. Inflammasome in platelets: allying coagulation, and inflammation in infectious, and sterile diseases? Mediators Inflamm 2015; 2015: 435783
128. Lee HM, Kim JJ, Kim HJ, et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 2013; 62: 194-204
129. Dixit VD. Nlrp3 inflammasome activation in type 2 diabetes: is it clinically relevant? Diabetes 2013; 62: 22-24
130. Ruscitti P, Cipriani P, Di Benedetto P, et al. Monocytes from patients with rheumatoid arthritis, and type 2 diabetes mellitus display an increased production of interleukin (IL)-1beta via the nucleotidebinding domain, and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol 2015; 182: 35-44
131. L'Homme L, Esser N, Riva L, et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res 2013; 54: 2998-3008
132. Zheng F, Xing S, Gong Z, et al. NLRP3 inflammasomes show high expression in aorta of patients with atherosclerosis. Heart Lung Circ 2013; 22: 746-750
133. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis, and activated by cholesterol crystals. Nature 2010; 464: 1357-1361
134. Murphy AJ, Kraakman MJ, Kammoun HL, et al. IL-18 Production from the NLRP1 inflammasome prevents obesity, and metabolic syndrome. Cell Metab 2016; 23: 155-164
135. Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation, and insulin resistance. Nat Med 2011; 17: 179-188
136. Villegas LR, Kluck D, Field C, et al. Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome. Antioxid Redox Signal 2013; 18: 1753-1764
137. Krishnan SM, Dowling JK, Ling YH, et al. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol 2016; 173: 752-765
138. Qi J, Yu XJ, Shi XL, et al. NF-kappaB blockade in hypothalamic paraventricular nucleus inhibits highsalt-induced hypertension through NLRP3, and caspase-1. Cardiovasc Toxicol. Epub ahead of print 5 October 2015. DOI: 10.1007/s12012-015-9344-9
139. Kolly L, Karababa M, Joosten LA, et al. Inflammatory role of ASC in antigen-induced arthritis is independent of caspase-1, NALP-3, and IPAF. J Immunol 2009; 183: 4003-4012
140. Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241
141. Zhou R, Tardivel A, Thorens B, et al. Thioredoxininteracting protein links oxidative stress to inflammasome activation. Nat Immunol 2010; 11: 136-140
142. Warnatsch A, Ioannou M, Wang Q, et al. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 2015; 349: 316-320
143. Abderrazak A, Couchie D, Mahmood DF, et al. Antiinflammatory, and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet. Circulation 2015; 131: 1061-1070
144. Peng K, Liu L, Wei D, et al. P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int J Mol Med 2015; 35: 1179-1188
145. Yin Z, Deng T, Peterson LE, et al. Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation. Mol Cell Endocrinol 2014; 394: 80-87
146. Rainone V, Schneider L, Saulle I, et al. Upregulation of inflammasome activity, and increased gut permeability are associated with obesity in children, and adolescents. Int J Obes (Lond)2016
147. Bando S, Fukuda D, Soeki T, et al. Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis. Atherosclerosis 2015; 242: 407-414
148. Honda H, Nagai Y, Matsunaga T, et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation, and diet-induced adipose tissue inflammation. J Leukoc Biol 2014; 96: 1087-1100
149. Liu P, Xie Q, Wei T, et al. Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats. Biochem Biophys Res Commun 2015; 468: 319-325
150. Yan Y, Jiang W, Spinetti T, et al. Omega-3 fatty acids prevent inflammation, and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 2013; 38: 1154-1163
151. Wen H, Gris D, Lei Y, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011; 12: 408-415
152. Netea MG, and Joosten LA. The NLRP1-IL18 connection: A stab in the back of obesity-induced inflammation. Cell Metab 2016; 23: 6-7
153. Dalekos GN, Elisaf M, Bairaktari E, et al. Increased serum levels of interleukin-1beta in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? J Lab Clin Med 1997; 129: 300-308
154. Tang B, Chen GX, Liang MY, et al. Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats. Int J Cardiol 2015; 180: 134-141
155. Cero FT, Hillestad V, Sjaastad I, et al. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2015; 309: L378-L387
156. Qi J, Zhao XF, Yu XJ, et al. Targeting Interleukin-1 beta to suppress sympathoexcitation in hypothalamic paraventricular nucleus in dahl salt-sensitive hypertensive rats. Cardiovasc Toxicol 2015; 16: 298-306
157. Wiseman SJ, Ralston SH, and Wardlaw JM. Cerebrovascular disease in rheumatic diseases: A systematic review, and meta-analysis. Stroke 2016; 47: 943-950
158. Nguyen-Oghalai TU, Wu H, McNearney TA, et al. Functional outcome after stroke in patients with rheumatoid arthritis, and systemic lupus erythematosus. Arthritis Rheum 2008; 59: 984-988
159. Clarson LE, Hider SL, Belcher J, et al. Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK clinical practice research datalink. Ann Rheum Dis 2015; 74: 642-647
160. Seminog OO, and Goldacre MJ. Gout as a risk factor for myocardial infarction, and stroke in England: evidence from record linkage studies. Rheumatology (Oxford) 2013; 52: 2251-2259
161. Lin YH, Hsu HL, Huang YC, et al. Gouty arthritis in acute cerebrovascular disease. Cerebrovasc Dis 2009; 28: 391-396
162. So A, De Smedt T, Revaz S, et al. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007; 9: R28
163. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009; 68: 1613-1617
164. Mathews RJ, Robinson JI, Battellino M, et al. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA, and response to anti-TNF treatment. Ann Rheum Dis 2014; 73: 1202-1210
165. Yamazaki H, Takeoka M, Kitazawa M, et al. ASC plays a role in the priming phase of the immune response to type II collagen in collagen-induced arthritis. Rheumatol Int 2012; 32: 1625-1632
166. Maheshwari P, and Eslick GD. Bacterial infection, and Alzheimer's disease: a meta-analysis. J Alzheimers Dis 2015; 43: 957-966
167. Miller EC, and Elkind MS. Infection, and stroke: an update on recent progress. Curr Neurol Neurosci Rep 2016; 16: 2
168. Hoegen T, Tremel N, Klein M, et al. The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis, and is activated through ATPdependent lysosomal cathepsin B release. J Immunol 2011; 187: 5440-5451
169. Geldhoff M, Mook-Kanamori BB, Brouwer MC, et al. Inflammasome activation mediates inflammation, and outcome in humans, and mice with pneumococcal meningitis. BMC Infect Dis 2013; 13: 358
170. Dumas A, Amiable N, de Rivero Vaccari JP, et al. The inflammasome pyrin contributes to pertussis toxin-induced IL-1beta synthesis, neutrophil intravascular crawling, and autoimmune encephalomyelitis. PLoS Pathog 2014; 10: e1004150
171. Maltez VI, and Miao EA. Reassessing the evolutionary importance of inflammasomes. J Immunol 2016; 196: 956-962
172. Zhang D, Yan H, Hu Y, et al. Increased expression of NLRP3 inflammasome in wall of ruptured, and unruptured human cerebral aneurysms: Preliminary results. J Stroke Cerebrovasc Dis 2015; 24: 972-979
173. Roberts RL, Van Rij AM, Phillips LV, et al. Interaction of the inflammasome genes CARD8, and NLRP3 in abdominal aortic aneurysms. Atherosclerosis 2011; 218: 123-126
174. Feng L, Chen Y, Ding R, et al. P2X7R blockade prevents NLRP3 inflammasome activation, and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation 2015; 12: 190
175. Ma Q, Chen S, Hu Q, et al. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol 2014; 75: 209-219
176. Rajamaki K, Nordstrom T, Nurmi K, et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem 2013; 288: 13410-13419
177. Liao KC, and Mogridge J. Activation of the Nlrp1b inflammasome by reduction of cytosolic ATP. Infect Immun 2013; 81: 570-579
178. Munoz-Planillo R, Kuffa P, Martinez-Colon G, et al. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins, and particulate matter. Immunity 2013; 38: 1142-1153
179. Petrilli V, Papin S, Dostert C, et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 2007; 14: 1583-1589
180. Adamczak S, Dale G, de Rivero Vaccari JP, et al. Inflammasome proteins in cerebrospinal fluid of braininjured patients as biomarkers of functional outcome: clinical article. J Neurosurg 2012; 117: 1119-1125
181. de Rivero Vaccari JP, Brand F III, Adamczak S, et al. Exosome-mediated inflammasome signaling after central nervous system injury. J Neurochem 2016; 136 Suppl 1: 39-48
182. Liu HD, Li W, Chen ZR, et al. Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res 2013; 38: 2072-2083
183. Hanamsagar R, Aldrich A, and Kielian T. Critical role for the AIM2 inflammasome during acute CNS bacterial infection. J Neurochem 2014; 129: 704-711
184. Jamilloux Y, Pierini R, Querenet M, et al. Inflammasome activation restricts Legionella pneumophila replication in primary microglial cells through flagellin detection. Glia 2013; 61: 539-549
185. Saresella M, , La Rosa F, Piancone F, et al. The NLRP3, and NLRP1 inflammasomes are activated in Alzheimer's disease. Mol Neurodegener 2016; 11: 23
186. Pontillo A, Catamo E, Arosio B, et al. NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis Assoc Disord 2012; 26: 277-281
187. Yuan B, Shen H, Lin L, et al. Recombinant adenovirus encoding NLRP3 RNAi attenuate inflammation, and brain injury after intracerebral hemorrhage. J Neuroimmunol 2015; 287: 71-75
188. Li J, Chen J, Mo H, et al. Minocycline protects against NLRP3 inflammasome-induced inflammation, and P53-associated apoptosis in early brain injury after subarachnoid hemorrhage. Mol Neurobiol 2015; 53: 2668-2678
189. Bonora M, Wieckowsk MR, Chinopoulos C, et al. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene 2015; 34: 1608
190. Horng T. Calcium signaling, and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol 2014; 35: 253-261
191. Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 2012; 36: 401-414
192. Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011; 12: 222-230
193. Frank MG, Weber MD, Fonken LK, et al. The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory, and microglial priming: A role for the NLRP3 inflammasome. Brain Behav Immun 2015; 55: 215-224
194. Bargiotas P, Krenz A, Hormuzdi SG, et al. Pannexins in ischemia-induced neurodegeneration. Proc Natl Acad Sci USA 2011; 108: 20772-20777
195. Cisneros-Mejorado A, Gottlieb M, Cavaliere F, et al. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage. J Cereb Blood Flow Metab 2015; 35: 843-850
196. Bauernfeind F, Bartok E, Rieger A, et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol 2011; 187: 613-617
197. Ystgaard MB, Sejersted Y, Loberg EM, et al. Early upregulation of NLRP3 in the brain of neonatal mice exposed to hypoxia-ischemia: No early neuroprotective effects of NLRP3 deficiency. Neonatology 2015; 108: 211-219
198. Blum-Degen D, Muller T, Kuhn W, et al. Interleukin-1 beta, and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's, and de novo Parkinson's disease patients. Neurosci Lett 1995; 202: 17-20
199. Shaftel SS, Carlson TJ, Olschowka JA, et al. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration, and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci 2007; 27: 9301-9309
200. Ghosh S, Wu MD, Shaftel SS, et al. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci 2013; 33: 5053-5064
201. Zhang P, Shao XY, Qi GJ, et al. Cdk5-dependent activation of neuronal inflammasomes in Parkinson's disease. Mov Disord 2016; 31: 366-376
202. Holscher C. Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans 2011; 39: 891-897
203. Vagelatos NT, and Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev 2013; 35: 152-160
204. Rapsinski GJ, Wynosky-Dolfi MA, Oppong GO, et al. Toll-like receptor 2, and NLRP3 cooperate to recognize a functional bacterial amyloid, curli. Infect Immun 2015; 83: 693-701
205. Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010; 11: 897-904
206. Niemi K, Teirila L, Lappalainen J, et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor, and a cathepsin B-sensitive pathway. J Immunol 2011; 186: 6119-6128
207. Wang JG, Williams JC, Davis BK, et al. Monocytic microparticles activate endothelial cells in an IL-1betadependent manner. Blood 2011; 118: 2366-2374
208. Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat Med 2016; 22: 516-523
209. Houlden A, Goldrick M, Brough D, et al. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity, and mucoprotein production. Brain Behav Immun. Epub ahead of print 6 April 2016. DOI: 10.1016/j.bbi.2016.04.003
210. Caso JR, Hurtado O, Pereira MP, et al. Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome. Am J Physiol Regul Integr Comp Physiol 2009; 296: R979-R985
211. Wong ML, Inserra A, Lewis MD, et al. Inflammasome signaling affects anxiety-and depressive-like behavior, and gut microbiome composition. Mol Psychiatry 2016; 21: 797-805
212. Mawhinney LJ, de Rivero Vaccari JP, Dale GA, et al. Heightened inflammasome activation is linked to agerelated cognitive impairment in Fischer 344 rats. BMC Neurosci 2011; 12: 123
213. Youm YH, Grant RW, McCabe LR, et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 2013; 18: 519-532
214. Brough D, Rothwell NJ, and Allan SM. Interleukin-1 as a pharmacological target in acute brain injury. Exp Physiol 2015; 100: 1488-1494
215. Maysami S, Wong R, Pradillo JM, et al. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke. J Cereb Blood Flow Metab 2016; 36: 596-605
216. Abbate A, Kontos MC, Abouzaki NA, et al. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART, and VCUART2 pilot studies). Am J Cardiol 2015; 115: 288-292
217. Helmy A, Guilfoyle MR, Carpenter KL, et al. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab 2014; 34: 845-851
218. Emsley HC, Smith CJ, Georgiou RF, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005; 76: 1366-1372
219. Baldwin AG, Brough D, and Freeman S. Inhibiting the inflammasome: A chemical perspective. J Med Chem 2016; 59: 1691-1710
220. Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015; 21: 248-255
221. Fowler BJ, Gelfand BD, Kim Y, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic antiinflammatory activity. Science 2014; 346: 1000-1003