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Inflammasome Signaling in the Aging Brain and Age-Related Neurodegenerative Diseases

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Abstract

Inflammasomes are intracellular protein complexes, members of the innate immune system, and their activation and regulation play an essential role in maintaining homeostatic conditions against exogenous and endogenous stimuli. Inflammasomes occur as cytosolic proteins and assemble into a complex during the recognition of pathogen-associated or danger-associated molecular patterns by pattern-recognition receptors in host cells. The formation of the inflammasome complex elicits signaling molecules of proinflammatory cytokines such as interleukin-1β and interleukin 18 via activation of caspase-1 in the canonical inflammasome pathway whereas caspase-11 in the case of a mouse and caspase-4 and caspase-5 in the case of humans in the non-canonical inflammasome pathway, resulting in pyroptotic or inflammatory cell death which ultimately leads to neuroinflammation and neurodegenerative diseases. Inflammasome activation, particularly in microglial cells and macrophages, has been linked to aging as well as age-related neurodegenerative diseases. The accumulation of abnormal/ misfolded proteins acts as a ligand for inflammasome activation in neurodegenerative diseases. Although recent studies have revealed the inflammasomes’ functionality in both in vitro and in vivo models, many inflammasome signaling cascade activations during biological aging, neuroinflammation, and neurodegeneration are still ambiguous. In this review, we comprehensively unveil the cellular and molecular mechanisms of inflammasome activation during neuronal aging and age-related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, prion disease, and amyotrophic lateral sclerosis.

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Abbreviations

AIM2:

Absent-in-melanoma 2

AD:

Alzheimer’s disease

APP:

Amyloid-beta precursor protein

ASC:

Apoptosis-associated speck-like protein containing a caspase-recruitment domain

CCL3:

C-C motif chemokine ligand 3

PrPc :

Cellular prion protein

CSF:

Cerebrospinal fluid

DAMP:

Damage-associated molecular pattern

GSDMD:

Gasdermin D

IFN:

Interferon

IL:

Interleukin

IL-1R:

IL-1 receptor

LRR:

Leucine-rich repeat

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B

NLR:

Nod-like receptor

NLRP:

Nod-like receptor protein

NLRP3:

NLR family pyrin domain containing 3

NLRC4:

NLR family CARD domain-containing protein 4

NOD:

Nucleotide-binding oligomerization domain

PAMP:

Pathogen-associated molecular pattern

PRR:

Pattern-recognition receptor

P2RX7:

P2X purinoceptor 7

PYD:

Pyrin domain

PrPsc :

Scrapie isoform of the prion protein

TLR:

Toll-like receptor

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

References

  1. Ottis P, Koppe K, Onisko B, Dynin I, Arzberger T, Kretzschmar H, Requena JR, Silva CJ et al (2012) Human and rat brain lipofuscin proteome. Proteomics 12(15–16):2445–2454. https://doi.org/10.1002/pmic.201100668

    Article  CAS  PubMed  Google Scholar 

  2. Clewett DV, Lee TH, Greening S, Ponzio A, Margalit E, Mather M (2016) Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiol Aging 37:117–126. https://doi.org/10.1016/j.neurobiolaging.2015.09.019

    Article  CAS  PubMed  Google Scholar 

  3. Latz E, Duewell P (2018) NLRP3 inflammasome activation in inflammaging. Semin Immunol 40:61–73. https://doi.org/10.1016/j.smim.2018.09.001

    Article  CAS  PubMed  Google Scholar 

  4. Singh T, Newman AB (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10(3):319–329. https://doi.org/10.1016/j.arr.2010.11.002

    Article  CAS  PubMed  Google Scholar 

  5. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14(10):576–590. https://doi.org/10.1038/s41574-018-0059-4

    Article  CAS  PubMed  Google Scholar 

  6. Franceschi C, Zaikin A, Gordleeva S, Ivanchenko M, Bonifazi F, Storci G, Bonafe M (2018) Inflammaging 2018: an update and a model. Semin Immunol 40:1–5. https://doi.org/10.1016/j.smim.2018.10.008

    Article  PubMed  Google Scholar 

  7. Calabrese V, Santoro A, Monti D, Crupi R, Di Paola R, Latteri S, Cuzzocrea S, Zappia M et al (2018) Aging and Parkinson’s disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radical Biol Med 115:80–91. https://doi.org/10.1016/j.freeradbiomed.2017.10.379

    Article  CAS  Google Scholar 

  8. Cicolari S, Catapano AL, Magni P (2021) Inflammaging and neurodegenerative diseases: role of NLRP3 inflammasome activation in brain atherosclerotic vascular disease. Mech Ageing Dev 195:111467. https://doi.org/10.1016/j.mad.2021.111467

    Article  CAS  PubMed  Google Scholar 

  9. Dugger BN, Dickson DW (2017) Pathology of neurodegenerative diseases. Cold Spring Harbor perspectives in biology 9(7):a028035. https://doi.org/10.1101/cshperspect.a028035

  10. Heneka MT, McManus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19(10):610–621. https://doi.org/10.1038/s41583-018-0055-7

    Article  CAS  PubMed  Google Scholar 

  11. Kumar M, Roe K, Orillo B, Muruve DA, Nerurkar VR, Gale M Jr, Verma S (2013) Inflammasome adaptor protein apoptosis-associated speck-like protein containing CARD (ASC) is critical for the immune response and survival in west Nile virus encephalitis. J Virol 87(7):3655–3667. https://doi.org/10.1128/JVI.02667-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fink SL, Bergsbaken T, Cookson BT (2008) Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci U S A 105(11):4312–4317. https://doi.org/10.1073/pnas.0707370105

    Article  PubMed  PubMed Central  Google Scholar 

  13. Khare S, Luc N, Dorfleutner A, Stehlik C (2010) Inflammasomes and their activation. Crit Rev Immunol 30(5):463–487. https://doi.org/10.1615/critrevimmunol.v30.i5.50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG, Ramos-Escobar N (2019) Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol 10:1008. https://doi.org/10.3389/fphar.2019.01008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yoneyama M, Fujita T (2008) Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity 29(2):178–181. https://doi.org/10.1016/j.immuni.2008.07.009

    Article  CAS  PubMed  Google Scholar 

  16. Benko S, Philpott DJ, Girardin SE (2008) The microbial and danger signals that activate Nod-like receptors. Cytokine 43(3):368–373. https://doi.org/10.1016/j.cyto.2008.07.013

    Article  CAS  PubMed  Google Scholar 

  17. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458(7237):514–518. https://doi.org/10.1038/nature07725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13(6):397–411. https://doi.org/10.1038/nri3452

    Article  CAS  PubMed  Google Scholar 

  19. Hu MY, Lin YY, Zhang BJ, Lu DL, Lu ZQ, Cai W (2019) Update of inflammasome activation in microglia/macrophage in aging and aging-related disease. CNS Neurosci Ther 25(12):1299–1307. https://doi.org/10.1111/cns.13262

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mammana S, Fagone P, Cavalli E, Basile MS, Petralia MC, Nicoletti F, Bramanti P, Mazzon E (2018) The role of macrophages in neuroinflammatory and neurodegenerative pathways of Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis: pathogenetic cellular effectors and potential therapeutic targets. Int J Mol Sci 19(3): 831. https://doi.org/10.3390/ijms19030831

  21. Davis EJ, Foster TD, Thomas WE (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34(1):73–78. https://doi.org/10.1016/0361-9230(94)90189-9

    Article  CAS  PubMed  Google Scholar 

  22. Marin-Aguilar F, Ruiz-Cabello J, Cordero MD (2018) Aging and the inflammasomes. Exp Suppl 108:303–320. https://doi.org/10.1007/978-3-319-89390-7_13

    Article  CAS  PubMed  Google Scholar 

  23. Mejias NH, Martinez CC, Stephens ME, de Rivero Vaccari JP (2018) Contribution of the inflammasome to inflammaging. J Inflamm (Lond) 15:23. https://doi.org/10.1186/s12950-018-0198-3

    Article  CAS  Google Scholar 

  24. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S et al (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18(4):519–532. https://doi.org/10.1016/j.cmet.2013.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sebastian-Valverde M, Pasinetti GM (2020) The NLRP3 inflammasome as a critical actor in the inflammaging process. Cells 9(6):1552. https://doi.org/10.3390/cells9061552

  26. Labzin LI, Heneka MT, Latz E (2018) Innate immunity and neurodegeneration. Annu Rev Med 69:437–449. https://doi.org/10.1146/annurev-med-050715-104343

    Article  CAS  PubMed  Google Scholar 

  27. Furman D, Jojic V, Kidd B, Shen-Orr S, Price J, Jarrell J, Tse T, Huang H et al (2013) Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Mol Syst Biol 9:659. https://doi.org/10.1038/msb.2013.15

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G (2011) Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev 11(2):149–153. https://doi.org/10.1016/j.autrev.2011.09.005

    Article  CAS  PubMed  Google Scholar 

  29. Scrivo R, Vasile M, Bartosiewicz I, Valesini G (2011) Inflammation as “common soil” of the multifactorial diseases. Autoimmun Rev 10(7):369–374. https://doi.org/10.1016/j.autrev.2010.12.006

    Article  PubMed  Google Scholar 

  30. Wang WY, Tan MS, Yu JT, Tan L (2015) Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10):136. https://doi.org/10.3978/j.issn.2305-5839.2015.03.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885(1):25–31. https://doi.org/10.1016/s0006-8993(00)02883-3

    Article  CAS  PubMed  Google Scholar 

  32. Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161. https://doi.org/10.1146/annurev-cellbio-101011-155745

    Article  CAS  PubMed  Google Scholar 

  33. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40(2):140–155. https://doi.org/10.1002/glia.10161

    Article  PubMed  Google Scholar 

  34. Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214(5):1351–1370. https://doi.org/10.1084/jem.20150237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Theriault P, ElAli A, Rivest S (2015) The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimers Res Ther 7(1):41. https://doi.org/10.1186/s13195-015-0125-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ou Z, Zhou Y, Wang L, Xue L, Zheng J, Chen L, Tong Q (2021) NLRP3 inflammasome inhibition prevents alpha-synuclein pathology by relieving autophagy dysfunction in chronic MPTP-treated NLRP3 knockout mice. Mol Neurobiol 58(4):1303–1311. https://doi.org/10.1007/s12035-020-02198-5

    Article  CAS  PubMed  Google Scholar 

  37. Han C, Yang Y, Guan Q, Zhang X, Shen H, Sheng Y, Wang J, Zhou X, Li W, Guo L, Jiao Q (2020) New mechanism of nerve injury in Alzheimer’s disease: beta-amyloid-induced neuronal pyroptosis. J Cell Mol Med 24(14):8078–8090. https://doi.org/10.1111/jcmm.15439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lindenberg R (1990) Neuropathological diagnosis of Alzheimer disease. J Neuropathol Exp Neurol 49(5):535–537. https://doi.org/10.1097/00005072-199009000-00010

    Article  CAS  PubMed  Google Scholar 

  39. Yiannopoulou KG, Papageorgiou SG (2020) Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst Dis 12:1179573520907397. https://doi.org/10.1177/1179573520907397

    Article  PubMed  PubMed Central  Google Scholar 

  40. Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416. https://doi.org/10.1038/nri1843

    Article  CAS  PubMed  Google Scholar 

  41. Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295(5556):851–855. https://doi.org/10.1126/science.1067484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9(8):857–865. https://doi.org/10.1038/ni.1636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Murphy N, Grehan B, Lynch MA (2014) Glial uptake of amyloid beta induces NLRP3 inflammasome formation via cathepsin-dependent degradation of NLRP10. NeuroMol Med 16(1):205–215. https://doi.org/10.1007/s12017-013-8274-6

    Article  CAS  Google Scholar 

  44. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R et al (2016) The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener 11:23. https://doi.org/10.1186/s13024-016-0088-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Simard AR, Rivest S (2006) Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer’s disease. Mol Psychiatry 11(4):327–335. https://doi.org/10.1038/sj.mp.4001809

    Article  CAS  PubMed  Google Scholar 

  46. Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24(3):173–182. https://doi.org/10.1016/0165-5728(89)90115-x

    Article  CAS  PubMed  Google Scholar 

  47. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678. https://doi.org/10.1038/nature11729

    Article  CAS  PubMed  Google Scholar 

  48. Martin E, Amar M, Dalle C, Youssef I, Boucher C, Le Duigou C, Bruckner M, Prigent A et al (2019) New role of P2X7 receptor in an Alzheimer’s disease mouse model. Mol Psychiatry 24(1):108–125. https://doi.org/10.1038/s41380-018-0108-3

    Article  CAS  PubMed  Google Scholar 

  49. Gemma C, Bickford PC (2007) Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Rev Neurosci 18(2):137–148. https://doi.org/10.1515/revneuro.2007.18.2.137

    Article  CAS  PubMed  Google Scholar 

  50. Bourgognon JM, Cavanagh J (2020) The role of cytokines in modulating learning and memory and brain plasticity. Brain Neurosci Adv 4:2398212820979802. https://doi.org/10.1177/2398212820979802

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang Z, Liu D, Wang F, Liu S, Zhao S, Ling EA, Hao A (2012) Saturated fatty acids activate microglia via Toll-like receptor 4/NF-kappaB signalling. Br J Nutr 107(2):229–241. https://doi.org/10.1017/S0007114511002868

    Article  CAS  PubMed  Google Scholar 

  52. Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ (2012) Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J Neurochem 120(6):1060–1071. https://doi.org/10.1111/j.1471-4159.2012.07660.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu L, Chan C (2014) IPAF inflammasome is involved in interleukin-1beta production from astrocytes, induced by palmitate; implications for Alzheimer’s Disease. Neurobiol Aging 35(2):309–321. https://doi.org/10.1016/j.neurobiolaging.2013.08.016

    Article  CAS  PubMed  Google Scholar 

  54. Gcwensa NZ, Russell DL, Cowell RM, Volpicelli-Daley LA (2021) Molecular mechanisms underlying synaptic and axon degeneration in Parkinson’s disease. Front Cell Neurosci 15:626128. https://doi.org/10.3389/fncel.2021.626128

    Article  PubMed  PubMed Central  Google Scholar 

  55. Burke RE, O’Malley K (2013) Axon degeneration in Parkinson’s disease. Exp Neurol 246:72–83. https://doi.org/10.1016/j.expneurol.2012.01.011

    Article  CAS  PubMed  Google Scholar 

  56. Anderson FL, Coffey MM, Berwin BL, Havrda MC (2018) Inflammasomes: an emerging mechanism translating environmental toxicant exposure into neuroinflammation in Parkinson’s disease. Toxicol Sci 166(1):3–15. https://doi.org/10.1093/toxsci/kfy219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Voet S, Srinivasan S, Lamkanfi M, van Loo G (2019) Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med 11(6):e10248. https://doi.org/10.15252/emmm.201810248

  58. Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 150(8):963–976. https://doi.org/10.1038/sj.bjp.0707167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker RA, Cicchetti F (2014) Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease. Int J Neuropsychopharmacol 18(6):pyu103. https://doi.org/10.1093/ijnp/pyu103

  60. Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32:367–402. https://doi.org/10.1146/annurev-immunol-032713-120240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Litteljohn D, Cummings A, Brennan A, Gill A, Chunduri S, Anisman H, Hayley S (2010) Interferon-gamma deficiency modifies the effects of a chronic stressor in mice: implications for psychological pathology. Brain Behav Immun 24(3):462–473. https://doi.org/10.1016/j.bbi.2009.12.001

    Article  CAS  PubMed  Google Scholar 

  62. Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 16(6):724–739. https://doi.org/10.1006/mcne.2000.0914

    Article  CAS  PubMed  Google Scholar 

  63. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291. https://doi.org/10.1212/wnl.38.8.1285

    Article  CAS  PubMed  Google Scholar 

  64. Lawana V, Singh N, Sarkar S, Charli A, Jin H, Anantharam V, Kanthasamy AG, Kanthasamy A (2017) Involvement of c-Abl kinase in microglial activation of NLRP3 inflammasome and impairment in autolysosomal system. J Neuroimmune Pharmacol 12(4):624–660. https://doi.org/10.1007/s11481-017-9746-5

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhang P, Shao XY, Qi GJ, Chen Q, Bu LL, Chen LJ, Shi J, Ming J et al (2016) Cdk5-dependent activation of neuronal inflammasomes in Parkinson’s disease. Mov Disord 31(3):366–376. https://doi.org/10.1002/mds.26488

    Article  CAS  PubMed  Google Scholar 

  66. Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, de Bernard M (2013) Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8(1):e55375. https://doi.org/10.1371/journal.pone.0055375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202(1–2):17–20. https://doi.org/10.1016/0304-3940(95)12192-7

    Article  CAS  PubMed  Google Scholar 

  68. Qin XY, Zhang SP, Cao C, Loh YP, Cheng Y (2016) Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol 73(11):1316–1324. https://doi.org/10.1001/jamaneurol.2016.2742

    Article  PubMed  Google Scholar 

  69. Fan Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y, Ma JH, Wang XM (2020) Systemic activation of NLRP3 inflammasome and plasma alpha-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuroinflammation 17(1):11. https://doi.org/10.1186/s12974-019-1670-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 180(2):147–150. https://doi.org/10.1016/0304-3940(94)90508-8

    Article  CAS  PubMed  Google Scholar 

  71. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R (2015) Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160(1–2):62–73. https://doi.org/10.1016/j.cell.2014.11.047

    Article  CAS  PubMed  Google Scholar 

  72. Nopoulos PC (2016) Huntington disease: a single-gene degenerative disorder of the striatum. Dialogues Clin Neurosci 18(1):91–98

    Article  PubMed  PubMed Central  Google Scholar 

  73. Roos RA (2010) Huntington’s disease: a clinical review. Orphanet J Rare Dis 5:40. https://doi.org/10.1186/1750-1172-5-40

    Article  PubMed  PubMed Central  Google Scholar 

  74. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE et al (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90(3):537–548. https://doi.org/10.1016/s0092-8674(00)80513-9

    Article  CAS  PubMed  Google Scholar 

  75. Sanchez Mejia RO, Friedlander RM (2001) Caspases in Huntington’s disease. Neuroscientist 7(6):480–489. https://doi.org/10.1177/107385840100700604

    Article  CAS  PubMed  Google Scholar 

  76. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS et al (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399(6733):263–267. https://doi.org/10.1038/20446

    Article  CAS  PubMed  Google Scholar 

  77. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L et al (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7):797–801. https://doi.org/10.1038/77528

    Article  CAS  PubMed  Google Scholar 

  78. Compston A (2004) The pathogenesis and basis for treatment in multiple sclerosis. Clin Neurol Neurosurg 106(3):246–248. https://doi.org/10.1016/j.clineuro.2004.02.007

    Article  PubMed  Google Scholar 

  79. Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393–407. https://doi.org/10.1038/nri2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, Wallstrom E, Lobell A et al (2008) Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol 84(5):1248–1255. https://doi.org/10.1189/jlb.1207844

    Article  CAS  PubMed  Google Scholar 

  81. Malhotra S, Costa C, Eixarch H, Keller CW, Amman L, Martinez-Banaclocha H, Midaglia L, Sarro E et al (2020) NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients. Brain 143(5):1414–1430. https://doi.org/10.1093/brain/awaa084

    Article  PubMed  Google Scholar 

  82. Inoue M, Shinohara ML (2013) NLRP3 Inflammasome and MS/EAE. Autoimmune Dis 2013:859145. https://doi.org/10.1155/2013/859145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mamik MK, Power C (2017) Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts. Brain 140(9):2273–2285. https://doi.org/10.1093/brain/awx133

    Article  PubMed  Google Scholar 

  84. Russi AE, Walker-Caulfield ME, Guo Y, Lucchinetti CF, Brown MA (2016) Meningeal mast cell-T cell crosstalk regulates T cell encephalitogenicity. J Autoimmun 73:100–110. https://doi.org/10.1016/j.jaut.2016.06.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Voet S, Mc Guire C, Hagemeyer N, Martens A, Schroeder A, Wieghofer P, Daems C, Staszewski O et al (2018) A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation. Nat Commun 9(1):2036. https://doi.org/10.1038/s41467-018-04376-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Keane RW, Dietrich WD, de Rivero Vaccari JP (2018) Inflammasome proteins as biomarkers of multiple sclerosis. Front Neurol 9:135. https://doi.org/10.3389/fneur.2018.00135

    Article  PubMed  PubMed Central  Google Scholar 

  87. Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, Vetter I, Dungan LS et al (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21(3):248–255. https://doi.org/10.1038/nm.3806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L (2007) Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 8(1):74–83. https://doi.org/10.1038/ni1415

    Article  CAS  PubMed  Google Scholar 

  89. Prusiner SB, Hsiao KK (1994) Human prion diseases. Ann Neurol 35(4):385–395. https://doi.org/10.1002/ana.410350404

    Article  CAS  PubMed  Google Scholar 

  90. Van Everbroeck B, Dobbeleir I, De Waele M, De Deyn P, Martin JJ, Cras P (2004) Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients. J Neurol 251(3):298–304. https://doi.org/10.1007/s00415-004-0311-9

    Article  PubMed  Google Scholar 

  91. Zhu C, Herrmann US, Falsig J, Abakumova I, Nuvolone M, Schwarz P, Frauenknecht K, Rushing EJ et al (2016) A neuroprotective role for microglia in prion diseases. J Exp Med 213(6):1047–1059. https://doi.org/10.1084/jem.20151000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shi F, Yang L, Kouadir M, Yang Y, Wang J, Zhou X, Yin X, Zhao D (2012) The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J Neuroinflammation 9:73. https://doi.org/10.1186/1742-2094-9-73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sasaki A, Hirato J, Nakazato Y (1993) Immunohistochemical study of microglia in the Creutzfeldt-Jakob diseased brain. Acta Neuropathol 86(4):337–344. https://doi.org/10.1007/BF00369445

    Article  CAS  PubMed  Google Scholar 

  94. Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8(3):449–457. https://doi.org/10.1111/j.1750-3639.1998.tb00167.x

    Article  CAS  PubMed  Google Scholar 

  95. Hafner-Bratkovic I, Bencina M, Fitzgerald KA, Golenbock D, Jerala R (2012) NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1beta and neuronal toxicity. Cell Mol Life Sci 69(24):4215–4228. https://doi.org/10.1007/s00018-012-1140-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Srivastava S, Katorcha E, Makarava N, Barrett JP, Loane DJ, Baskakov IV (2018) Inflammatory response of microglia to prions is controlled by sialylation of PrP(Sc). Sci Rep 8(1):11326. https://doi.org/10.1038/s41598-018-29720-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bellezza I, Grottelli S, Costanzi E, Scarpelli P, Pigna E, Morozzi G, Mezzasoma L, Peirce MJ et al (2018) Peroxynitrite activates the NLRP3 inflammasome cascade in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Mol Neurobiol 55(3):2350–2361. https://doi.org/10.1007/s12035-017-0502-x

    Article  CAS  PubMed  Google Scholar 

  98. Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, Wong PC, Brown RH Jr, Price DL et al (1994) Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci U S A 91(17):8292–8296. https://doi.org/10.1073/pnas.91.17.8292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gugliandolo A, Giacoppo S, Bramanti P, Mazzon E (2018) NLRP3 inflammasome activation in a transgenic amyotrophic lateral sclerosis model. Inflammation 41(1):93–103. https://doi.org/10.1007/s10753-017-0667-5

    Article  CAS  PubMed  Google Scholar 

  100. Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH Jr (1998) Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A 95(26):15763–15768. https://doi.org/10.1073/pnas.95.26.15763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Johann S, Heitzer M, Kanagaratnam M, Goswami A, Rizo T, Weis J, Troost D, Beyer C (2015) NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63(12):2260–2273. https://doi.org/10.1002/glia.22891

    Article  PubMed  Google Scholar 

  102. Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 107(29):13046–13050. https://doi.org/10.1073/pnas.1002396107

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lehmann S, Esch E, Hartmann P, Goswami A, Nikolin S, Weis J, Beyer C, Johann S (2018) Expression profile of pattern recognition receptors in skeletal muscle of SOD1((G93A)) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients. Neuropathol Appl Neurobiol 44(6):606–627. https://doi.org/10.1111/nan.12483

    Article  CAS  PubMed  Google Scholar 

  104. De Paola M, Sestito SE, Mariani A, Memo C, Fanelli R, Freschi M, Bendotti C, Calabrese V et al (2016) Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. Pharmacol Res 103:180–187. https://doi.org/10.1016/j.phrs.2015.11.020

    Article  CAS  PubMed  Google Scholar 

  105. Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A 105(40):15558–15563. https://doi.org/10.1073/pnas.0807419105

    Article  PubMed  PubMed Central  Google Scholar 

  106. Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol 4(4):389–398. https://doi.org/10.1007/s11481-009-9171-5

    Article  PubMed  Google Scholar 

  107. Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL et al (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 28(1):18–25. https://doi.org/10.1002/ana.410280106

    Article  CAS  PubMed  Google Scholar 

  108. Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, Chen FF, Jiang XD (2013) Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation 10:106. https://doi.org/10.1186/1742-2094-10-106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kerr N, Lee SW, Perez-Barcena J, Crespi C, Ibanez J, Bullock MR, Dietrich WD, Keane RW et al (2018) Inflammasome proteins as biomarkers of traumatic brain injury. PLoS ONE 13(12):e0210128. https://doi.org/10.1371/journal.pone.0210128

    Article  PubMed  PubMed Central  Google Scholar 

  110. Irrera N, Pizzino G, Calo M, Pallio G, Mannino F, Fama F, Arcoraci V, Fodale V et al (2017) Lack of the Nlrp3 inflammasome improves mice recovery following traumatic brain injury. Front Pharmacol 8:459. https://doi.org/10.3389/fphar.2017.00459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Weber JT (2012) Altered calcium signaling following traumatic brain injury. Front Pharmacol 3:60. https://doi.org/10.3389/fphar.2012.00060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Awasthi D, Kutz SC, Beuerman R, Nguyen D, Carey ME, Zeiller S (2003) Early gene expression in the rat cortex after experimental traumatic brain injury and hypotension. Neurosci Lett 345(1):29–32. https://doi.org/10.1016/s0304-3940(03)00497-x

    Article  CAS  PubMed  Google Scholar 

  113. Clausen F, Hanell A, Bjork M, Hillered L, Mir AK, Gram H, Marklund N (2009) Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur J Neurosci 30(3):385–396. https://doi.org/10.1111/j.1460-9568.2009.06820.x

    Article  PubMed  Google Scholar 

  114. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW (2012) Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg 117(6):1119–1125. https://doi.org/10.3171/2012.9.JNS12815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wallisch JS, Simon DW, Bayir H, Bell MJ, Kochanek PM, Clark RSB (2017) Cerebrospinal fluid NLRP3 is increased after severe traumatic brain injury in infants and children. Neurocrit Care 27(1):44–50. https://doi.org/10.1007/s12028-017-0378-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Piancone F, La Rosa F, Marventano I, Saresella M, Clerici M (2021) The role of the inflammasome in neurodegenerative diseases. Molecules 26(4):953. https://doi.org/10.3390/molecules26040953

  117. Duan Y, Kelley N, He Y (2020) Role of the NLRP3 inflammasome in neurodegenerative diseases and therapeutic implications. Neural Regen Res 15(7):1249–1250. https://doi.org/10.4103/1673-5374.272576

    Article  PubMed  PubMed Central  Google Scholar 

  118. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D’Agostino D, Planavsky N et al (2015) The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269. https://doi.org/10.1038/nm.3804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA et al (2010) Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. J Biol Chem 285(13):9792–9802. https://doi.org/10.1074/jbc.M109.082305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ahn H, Kim J, Jeung EB, Lee GS (2014) Dimethyl sulfoxide inhibits NLRP3 inflammasome activation. Immunobiology 219(4):315–322. https://doi.org/10.1016/j.imbio.2013.11.003

    Article  CAS  PubMed  Google Scholar 

  121. Inoue M, Williams KL, Oliver T, Vandenabeele P, Rajan JV, Miao EA, Shinohara ML (2012) Interferon-beta therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci Signal 5(225):ra38. https://doi.org/10.1126/scisignal.2002767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Isakov E, Weisman-Shomer P (1840) Benhar M (2014) Suppression of the pro-inflammatory NLRP3/interleukin-1beta pathway in macrophages by the thioredoxin reductase inhibitor auranofin. Biochim Biophys Acta 10:3153–3161. https://doi.org/10.1016/j.bbagen.2014.07.012

    Article  CAS  Google Scholar 

  123. Honda H, Nagai Y, Matsunaga T, Okamoto N, Watanabe Y, Tsuneyama K, Hayashi H, Fujii I et al (2014) Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J Leukoc Biol 96(6):1087–1100. https://doi.org/10.1189/jlb.3A0114-005RR

    Article  CAS  PubMed  Google Scholar 

  124. He Y, Varadarajan S, Munoz-Planillo R, Burberry A, Nakamura Y, Nunez G (2014) 3,4-methylenedioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem 289(2):1142–1150. https://doi.org/10.1074/jbc.M113.515080

    Article  CAS  PubMed  Google Scholar 

  125. Maier NK, Leppla SH, Moayeri M (2015) The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes. J Immunol 194(6):2776–2785. https://doi.org/10.4049/jimmunol.1401611

    Article  CAS  PubMed  Google Scholar 

  126. Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG (2014) Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345(6197):679–684. https://doi.org/10.1126/science.1254790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AAB, Butler MS, Rowe DB, O'Neill LA, Kanthasamy AG, Schroder K, Cooper MA, Woodruff TM (2018) Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10(465):eaah4066. https://doi.org/10.1126/scitranslmed.aah4066

  128. Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson AAB, Cooper MA, O’Neill LAJ, Lynch MA (2017) Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun 61:306–316. https://doi.org/10.1016/j.bbi.2016.12.014

    Article  CAS  PubMed  Google Scholar 

  129. La Rosa F, Saresella M, Marventano I, Piancone F, Ripamonti E, Al-Daghri N, Bazzini C, Zoia CP, Conti E, Ferrarese C, Clerici M (2019) Stavudine reduces NLRP3 inflammasome activation and modulates amyloid-beta autophagy. J Alzheimers Dis 72(2):401–412. https://doi.org/10.3233/JAD-181259

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the Department of Science and Technology, Government of India, for their support in the form of FIST Grant.

Funding

This work was supported by the Science & Engineering Research Board, Government of India (EMR/2017/002793); the University Grants Commission, Government of India (Startup Research Grant); and the Indian Council of Medical Research, Government of India (IRIS ID: 2020–5687).

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  1. Subhashini Brahadeeswaran and Narmadhaa Sivagurunathan contributed equally to this work.

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  1. Molecular Pharmacology and Toxicology Laboratory, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Neelakudi Campus, Thiruvarur, Tamil Nadu, 610005, India

    Subhashini Brahadeeswaran, Narmadhaa Sivagurunathan & Latchoumycandane Calivarathan

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LC outlined and structured the review; SB, NS and LC wrote the manuscript; NS and LC created the figures and tables; SB, NS, and LC proofed the text and edited the tables and figures. LC and NS revised the manuscript. All authors read and approve the final version of the manuscript at the time of submission.

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Brahadeeswaran, S., Sivagurunathan, N. & Calivarathan, L. Inflammasome Signaling in the Aging Brain and Age-Related Neurodegenerative Diseases. Mol Neurobiol 59, 2288–2304 (2022). https://doi.org/10.1007/s12035-021-02683-5

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