Age-associated diseases: the role of the inflammasome complex

• Lyudmila V. Gankovskaya
• Olga V. Artemyeva
• Vyacheslav V. Grechenko
• Ekaterina D. Nasaeva
• Elena M. Khasanova

Abstract

Inflammatory aging (inflammaging) is one of the manifestations of immunosenescence and is considered as an important risk factor for morbidity and mortality among the elderly. An important role in the development of chronic sterile inflammation, which underlies age-related pathology, is attributed to chronic activation of pattern recognition receptors of the innate immunity system and their signaling pathways, primarily by endogenous ligands. When these ligands bind to the matching TLR, the NF-κB signaling pathway – which is considered as a key pathway for the development of inflammaging – is activated.

Stimulation of the NLR leads to the formation of inflammasomes, one of the functions of which is the processing of pro-inflammatory cytokines to a biologically active form, which is also an important factor in inflammaging, and underlies the pathogenesis of various chronic diseases.

This review addresses the role of the inflammasome complex in regards to immunopathogenesis of the following age-related diseases: Alzheimer’s disease, Parkinson’s disease, type II diabetes mellitus, atherosclerosis, joint diseases. New data frames the NLRP3 inflammasome as the most significant factor in the development of age-related diseases.

The review outlines the contribution of other inflammasome complexes to the development of age-related diseases. Further study of mechanisms of inflammasome-mediated inflammaging should allow for identification of potential targets for the treatment of age-related diseases.

Keywords:immunosenescence; inflammaging; innate immunity; inflammasome complex; PAMP; DAMP; NLRP3; age-associated diseases; Alzheimer’s disease, Parkinson’s disease; type 2 diabetes mellitus; atherosclerosis

References

1. Artemyeva O.V., Gankovskaya L.V. Inflammaging as the basis of age-associated diseases. Med Immunol. 2020; 22 (3): 419–32. DOI: https://doi.org/10.15789/1563-0625-IAT-1938 (in Russian)

2. Artemyeva O.V., Grechenko V.V., Gromova T.V., Gankovskaya L.V. Frailty: a controversial role of inflammaging. Immunologiya. 2022; 43 (6): 746–56. DOI: https://doi.org/10.33029/0206-4952-2022-43-6-746-756 (in Russian)

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

4. Zhan X., Li Q., Xu G., Xiao X., Bai Z. The Mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors. Front Immunol. 2023; 13: 1109938. DOI: https://doi.org/10.3389/fimmu.2022.1109938

5. Pellegrini C., Fornai M., Antonioli L., Blandizzi C., Calderone V. Phytochemicals as novel therapeutic strategies for NLRP3 inflammasome-related neurological, metabolic, and inflammatory diseases. Int J Mol Sci. 2019; 20 (12): 2876. DOI: https://doi.org/10.3390/IJMS20122876

6. Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders. nature. 2017; 542 (7640): 177–85. DOI: https://doi.org/10.1038/nature21363

7. Franceschi C., Garagnani P., Parini P., Giuliani C., Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018; 14 (10): 576–90. DOI: https://doi.org/10.1038/s41574-018-0059-4

8. Fusco R., Siracusa R., Genovese T., Cuzzocrea S., Paola R. Di focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci. 2020; 21 (12): 1–25. DOI: https://doi.org/10.3390/ijms21124223

9. Wu K.K.L., Cheung S.W.M., Cheng K.K.Y. NLRP3 Inflammasome activation in adipose tissues and its implications on metabolic diseases. Int J Mol Sci. 2020; 21 (11): 1–22. DOI: https://doi.org/10.3390/ijms21114184

10. Lu S., Li Y., Qian Z., Zhao T., Feng Z., Weng X., Yu L. Role of the Inflammasome in insulin resistance and type 2 diabetes mellitus. Front Immunol. 2023; 14: 1052756. DOI: https://doi.org/10.3389/fimmu.2023.1052756

11. Pirzada R.H., Javaid N., Choi S. The roles of the NLRP3 inflammasome in neurodegenerative and metabolic diseases and in relevant advanced therapeutic interventions. Genes (Basel). 2020; 11 (2): 131. DOI: https://doi.org/10.3390/genes11020131

12. Anhê F.F., Jensen B.A.H., Varin T.V., Servant F., Van Blerk S., Richard D., Marceau S., Surette M., Biertho L., Lelouvier B., Schertzer J.D., Tchernof A., Marette A. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat Metab. 2020; 2 (3): 233–42. DOI: https://doi.org/10.1038/s42255-020-0178-9

13. Chen L., Liu C., Gao J., Xie Z., Chan L. W. C., Keating D. J., Yang Y., Sun J., Zhou F., Wei Y., Men X., Yang S. Inhibition of miro1 disturbs mitophagy and pancreatic β-cell function interfering insulin release via IRS-Akt-foxo1 in diabetes. Oncotarget. 2017; 8 (53): 90693–705. DOI: https://doi.org/10.18632/oncotarget.20963

14. Fu S., Liu L., Han L., Yu Y. Leptin promotes IL-18 secretion by activating the NLRP3 inflammasome in RAW 264.7 cells. Mol Med Rep. 2017; 16 (6): 9770–6. DOI: https://doi.org/10.3892/mmr.2017.7797

15. Kong X., Lu A.L., Yao X.M., Hua Q., Li X.Y., Qin L., Zhang H.M., Meng G.X., Su Q. Activation of NLRP3 inflammasome by advanced glycation end products promotes pancreatic islet damage. Oxid Med Cell Longev. 2017; 2017: 9692546. DOI: https://doi.org/10.1155/2017/9692546

16. Tsalamandris S., Antonopoulos A.S., Oikonomou E., Papamikroulis G. A., Vogiatzi G., Papaioannou S., Deftereos S., Tousoulis D. The role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol Rev. 2019; 14 (1): 50. DOI: https://doi.org/10.15420/ecr.2018.33.1

17. Ahmad R., Thomas R., Kochumon S., Sindhu S. Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity. immunity, inflamm dis. 2017; 5 (3): 318–35. DOI: https://doi.org/10.1002/iid3.170

18. Böni-Schnetzler M., Meier D.T. Islet Inflammation in Type 2 Diabetes. Semin Immunopathol. 2019; 41 (4): 501–3. DOI: https://doi.org/10.1007/s00281-019-00745-4

19. Hanslik K.L., Ulland T.K. The role of microglia and the Nlrp3 inflammasome in alzheimer’s disease. Front Neurol. 2020; 11: 570711. DOI: https://doi.org/10.3389/fneur.2020.570711

20. Friker L.L., Scheiblich H., Hochheiser I.V., Brinkschulte R., Riedel D., Latz E., Geyer M., Heneka M.T. β-Amyloid clustering around ASC fibrils boosts its toxicity in microglia. Cell Rep. 2020; 30 (11): 3743–54.e6. DOI: https://doi.org/10.1016/j.celrep.2020.02.025

21. Sudduth T.L., Schmitt F.A., Nelson P.T., Wilcock D.M. Neuroinflammatory phenotype in early Alzheimer’s dsease. Neurobiol Aging. 2013; 34 (4): 1051. DOI: https://doi.org/10.1016/j.neurobiolaging.2012.09.012

22. Stancu I.C., Cremers N., Vanrusselt H., Couturier J., Vanoosthuyse A., Kessels S., Lodder C., Brône B., Huaux F., Octave J. N., Terwel D., Dewachter I. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019; 137 (4): 599–617. DOI: https://doi.org/10.1007/s00401-018-01957-y

23. Ising C., Venegas C., Zhang S., Scheiblich H., Schmidt S.V., Vieira-Saecker A., Schwartz S., Albasset S., McManus R.M., Tejera D., Griep A., Santarelli F., Brosseron F., Opitz S., Stunden J., Merten M., Kayed R., Golenbock D.T., Blum D., Latz E., Buée L., Heneka M.T. NLRP3 Inflammasome activation drives Tau pathology. Nature. 2019; 575 (7784): 669–73. DOI: https://doi.org/10.1038/s41586-019-1769-z

24. Nasaeva E.D., Khasanova E.M., Gankovskaya L.V. Immunopathogenesis and target therapy of alzheimer’s disease. Immunologiya. 2023; 44 (2): 231–42. DOI: https://doi.org/10.33029/0206-4952-2023-44-2-231-242 (in Russian)

25. Anderson F.L., von Herrmann K.M., Andrew A.S., Kuras Y.I., Young A.L., Scherzer C.R., Hickey W.F., Lee S.L., Havrda M.C. Plasma-borne indicators of inflammasome activity in parkinson’s disease patients. NPJ Park Dis. 2021; 7 (1): 2. DOI: https://doi.org/10.1038/s41531-020-00147-6

26. Fan Z., Pan Y.T., Zhang Z.Y., Yang H., Yu S.Y., Zheng Y., Ma J.H., Wang X.M. Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in parkinson’s disease. J Neuroinflammation. 2020; 17 (1): 1–10. DOI: https://doi.org/10.1186/s12974-019-1670-6

27. Béraud D., Twomey M., Bloom B., Mittereder A., Ton V., Neitzke K., Chasovskikh S., Mhyre T.R., Maguire-Zeiss K. A. α-Synuclein alters Toll-like receptor expression. Front Neurosci. 2011; 5: 80. DOI: https://doi.org/10.3389/fnins.2011.00080

28. Liu H., Han X., Li Y., Zou H., Xie A. Association of P2X7 receptor gene polymorphisms with sporadic parkinson’s disease in a Han Chinese population. Neurosci Lett. 2013; 546: 42–5. DOI: https://doi.org/10.1016/j.neulet.2013.04.049

29. Van Weehaeghe D., Koole M., Schmidt M.E., Deman S., Jacobs A.H., Souche E., Serdons K., Sunaert S., Bormans G., Vandenberghe W., Van Laere K. [11C]JNJ54173717, a novel p2x7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers. Eur J Nucl Med Mol Imaging. 2019; 46 (10): 2051–64. DOI: https://doi.org/10.1007/s00259-019-04369-6

30. Codolo G., Plotegher N., Pozzobon T., Brucale M., Tessari I., Bubacco L., de Bernard M. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One. 2013; 8 (1): 55375. DOI: https://doi.org/10.1371/journal.pone.0055375

31. Ganjam G. K., Bolte K., Matschke L.A., Neitemeier S., Dolga A.M., Höllerhage M., Höglinger G.U., Adamczyk A., Decher N., Oertel W.H., Culmsee C. Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons. Cell Death Dis. 2019; 10 (11): 865. DOI: https://doi.org/10.1038/s41419-019-2091-2

32. Freeman D., Cedillos R., Choyke S., Lukic Z., McGuire K., Marvin S., Burrage A. M., Sudholt S., Rana A., O’Connor C., Wiethoff C. M., Campbell E. M. Alpha-Synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLoS One. 2013; 8 (4): 62143. DOI: https://doi.org/10.1371/journal.pone.0062143

33. Zhou Y., Lu M., Du R.H., Qiao C., Jiang C.Y., Zhang K.Z., Ding J. H., Hu G. MicroRNA-7 targets nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of parkinson’s disease. Mol Neurodegener. 2016; 11 (1): 1–15. DOI: https://doi.org/10.1186/s13024-016-0094-3

34. Mouton-Liger F., Rosazza T., Sepulveda-Diaz J., Ieang A., Hassoun S. M., Claire E., Mangone G., Brice A., Michel P.P., Corvol J.C., Corti O. Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an a20-dependent negative feedback loop. Glia. 2018; 66 (8): 1736–51. DOI: https://doi.org/10.1002/glia.23337

35. He Y., Chen Y., Yao L., Wang J., Sha X., Wang Y. The inflamm-aging model identifies key risk factors in atherosclerosis. Front Genet 2022; 13: 865827. DOI: https://doi.org/10.3389/fgene.2022.865827

36. Liao Y., Liu K., Zhu L. Emerging roles of inflammasomes in cardiovascular diseases. Front. Immunol. 2022; 13: 834289. DOI: https://doi.org/10.3389/fimmu.2022.834289

37. Gisterå A., Hansson G.K. The Immunology of atherosclerosis. Nat Rev Nephrol. 2017; 13 (6): 368–80. DOI: https://doi.org/10.1038/nrneph.2017.51

38. Netea M.G., Nold-Petry C.A., Nold M.F., Joosten L.A.B., Opitz B., Van Der Meer J.H.M., Van De Veerdonk F.L., Ferwerda G., Heinhuis B., Devesa I., Joel Funk C., Mason R.J., Kullberg B.J., Rubartelli A., Van Der Meer J.W.M., Dinarello C.A. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009; 113 (10): 2324–35. DOI: https://doi.org/10.1182/blood-2008-03-146720

39. Welsh P., Grassia G., Botha S., Sattar N., Maffia P. Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol. 2017; 174 (22): 3898–913. DOI: https://doi.org/10.1111/bph.13818

40. Afrasyab A., Qu P., Zhao Y., Peng K., Wang H., Lou D., Niu N., Yuan D. Correlation of NLRP3 with severity and prognosis of coronary atherosclerosis in acute coronary syndrome patients. Heart Vessels. 2016; 31 (8): 1218–29. DOI: https://doi.org/10.1007/S00380-015-0723-8

41. Borborema M.E. de A., Crovella S., Oliveira D., de Azevêdo Silva J. Inflammasome activation by NLRP1 and NLRC4 in patients with coronary stenosis. Immunobiology. 2020; 225 (3): 151940. DOI: https://doi.org/10.1016/J.IMBIO.2020.151940

42. Bleda S., De Haro J., Varela C., Ferruelo A., Acin F. Elevated levels of triglycerides and vldl-cholesterol provoke activation of Nlrp1 inflammasome in endothelial cells. Int J Cardiol. 2016; 220: 52–5. DOI: https://doi.org/10.1016/j.ijcard.2016.06.193

43. Paulin N., Viola J. R., Maas S. L., De Jong R., Fernandes-Alnemri T., Weber C., Drechsler M., Döring Y., Soehnlein O. Double-strand DNA sensing aim2 inflammasome regulates atherosclerotic plaque vulnerability. Circulation. 2018; 138 (3): 321–3. DOI: https://doi.org/10.1161/circulationaha.117.033098

44. Durga Devi T., Babu M., Mäkinen P., Kaikkonen M.U., Heinaniemi M., Laakso H., Ylä-Herttuala E., Rieppo L., Liimatainen T., Naumenko N., Tavi P., Ylä-Herttuala S. Aggravated postinfarct heart failure in type 2 diabetes is associated with impaired mitophagy and exaggerated inflammasome activation. Am J. Pathol. 2017; 187 (12): 2659–73. DOI: https://doi.org/10.1016/j.ajpath.2017.08.023

45. Olsen M.B., Gregersen I., Sandanger Ø., Yang K., Sokolova M., Halvorsen B.E., Gullestad L., Broch K., Aukrust P., Louwe M.C. Targeting the inflammasome in cardiovascular disease. JACC Basic to Transl Sci. 2022; 7 (1): 84–98. DOI: https://doi.org/10.1016/j.jacbts.2021.08.006

46. Van Der Heijden T., Kritikou E., Venema W., Van Duijn J., Van Santbrink P. J., Slütter B., Foks A. C., Bot I., Kuiper J. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein e-deficient mice-brief report. Arterioscler Thromb Vasc Biol. 2017; 37 (8): 1457–61. DOI: https://doi.org/10.1161/atvbaha.117.309575

47. Wohlford G.F., Van Tassell B.W., Billingsley H.E., Kadariya D., Canada J.M., Carbone S., Mihalick V.L., Bonaventura A., Vecchié A., Chiabrando J.G., Bressi E., Thomas G., Ho A.C., Marawan A.A., Dell M., Trankle C.R., Turlington J., Markley R., Abbate A. Phase 1B, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral NLRP3 inhibitor dapansutrile in subjects with NYHA II-III systolic heart failure. J Cardiovasc Pharmacol. 2020; 77 (1): 496–500. DOI: https://doi.org/10.1097/fjc.0000000000000931

48. Curtis E.M., van der Velde R., Moon R.J., van den Bergh J.P.W., Geusens P., de Vries F., van Staa T.P., Cooper C., Harvey N.C. Epidemiology of fractures in the United Kingdom 1988–2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone. 2016; 87: 19–26. DOI: https://doi.org/10.1016/j.bone.2016.03.006

49. Rosenberg J.H., Rai V., Dilisio M.F., Agrawal D.K. Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets. Mol Cell Biochem. 2017; 434 (1–2): 171–9. DOI: https://doi.org/10.1007/s11010-017-3047-4

50. Redlich K., Smolen J.S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012; 11 (3): 234–50. DOI: https://doi.org/10.1038/nrd3669

51. Youm Y.H., Grant R.W., McCabe L.R., Albarado D.C., Nguyen K.Y., Ravussin A., Pistell P., Newman S., Carter R., Laque A., Münzberg H., Rosen C.J., Ingram D.K., Salbaum J.M., Dixit V.D. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 2013; 18 (4): 519–32. DOI: https://doi.org/10.1016/j.cmet.2013.09.010

52. Alippe Y., Wang C., Ricci B., Xiao J., Qu C., Zou W., Novack D.V., Abu-Amer Y., Civitelli R., Mbalaviele G. Bone matrix components activate the NLRP3 inflammasome and promote osteoclast differentiation. Sci Rep. 2017; 7 (1): 6630. DOI: https://doi.org/10.1038/s41598-017-07014-0

53. Charatcharoenwitthaya N., Khosla S., Atkinson E.J., McCready L.K., Riggs B.L. Effect of dlockade of TNF-Alpha and Interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007; 22 (5): 7–9. DOI: https://doi.org/10.1359/jbmr.070207

54. Snouwaert J.N., Nguyen M.T., Repenning P.W., Dye R., Livingston E.W., Kovarova M., Moy S.S., Brigman B.E., Bateman T.A., Ting J.P.Y., Koller B.H. An NLRP3 mutation causes arthropathy and osteoporosis in humanized mice. Cell Rep. 2016; 17 (11): 3077–88. DOI: https://doi.org/10.1016/j.celrep.2016.11.052

55. Liu S., Du J., Li D., Yang P., Kou Y., Li C., Zhou Q., Lu Y., Hasegawa T., Li M. Oxidative stress induced pyroptosis leads to osteogenic dysfunction of MG63 cells. J Mol Histol. 2020; 51 (3): 221–32. DOI: https://doi.org/10.1007/s10735-020-09874-9

56. Tao Z., Wang J., Wen K., Yao R., Da W., Zhou S., Meng Y., Qiu S., Yang K., Zhu Y., Tao L. Pyroptosis in osteoblasts: a novel hypothesis underlying the pathogenesis of osteoporosis. Front Endocrinol. 2021; 11: 548812. DOI: https://doi.org/10.3389/fendo.2020.548812

57. Glyn-Jones S., Palmer A.J.R., Agricola R., Price A.J., Vincent T.L., Weinans H., Carr A.J. Osteoarthritis. Lancet. 2015; 386 (9991): 376–87. DOI: https://doi.org/10.1016/s0140-6736(14)60802-3

58. Clavijo-Cornejo D., Martínez-Flores K., Silva-Luna K., Martínez-Nava G.A., Fernández-Torres J., Zamudio-Cuevas Y., Guadalupe Santamaría-Olmedo M., Granados-Montiel J., Pineda C., López-Reyes A. The overexpression of NALP3 inflammasome in knee osteoarthritis is associated with synovial membrane prolidase and NADPH Oxidase 2. Oxid Med Cell Longev. 2016; 2016: 1472567. DOI: https://doi.org/10.1155/2016/1472567

59. Chen Z., Zhong H., Wei J., Lin S., Zong Z., Gong F., Huang X., Sun J., Li P., Lin H., Wei B., Chu J. Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis. Arthritis Res Ther. 2019; 21 (1): 1–13. DOI: https://doi.org/10.1186/s13075-019-2085-6/figures/10

60. Jin C., Frayssinet P., Pelker R., Cwirka D., Hu B., Vignery A., Eisenbarth S.C., Flavell R.A. NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci USA. 2011; 108 (36): 14867–72. DOI: https://doi.org/10.1073/pnas.1111101108/-/dcsupplemental

61. Martinon F., Pétrilli V., Mayor A., Tardivel A., Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440 (7081): 237–41. DOI: https://doi.org/10.1038/nature04516

62. Zhang Q.B., Qing Y.F., He Y.L., Xie W.G., Zhou J.G. Association of NLRP3 polymorphisms with susceptibility to primary gouty arthritis in a chinese han population. Clin Rheumatol. 2018; 37 (1): 235–44. DOI: https://doi.org/10.1007/s10067-017-3900-6

63. Dalbeth N., Gosling A.L., Gaffo A., Abhishek A. Gout Lancet. 2021; 397 (10287): 1843–55. DOI: https://doi.org/10.1016/s0140-6736(21)00569-9

64. Murakami T., Nakaminami Y., Takahata Y., Hata K., Nishimura R. Activation and function of NLRP3 inflammasome in bone and joint-related diseases. Int J Mol Sci. 2022; 23 (10): 5365. DOI: https://doi.org/10.3390/ijms23105365

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