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Aging and disease    2020, Vol. 11 Issue (4) : 756-762     DOI: 10.14336/AD.2020.0601
Opinion |
Age-induced NLRP3 Inflammasome Over-activation Increases Lethality of SARS-CoV-2 Pneumonia in Elderly Patients
Lara Pedro C1,2,3,*, Macías-Verde David1,2,3, Burgos-Burgos Javier1,2,3
1Hospital Universitario San Roque, Las Palmas, Spain
2Universidad Fernando Pessoa Canarias, Las Palmas, Spain
3Instituto Canario de Investigación del Cáncer, Tenerife, Spain
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Age is one of the most important prognostic factors associated to lethality in SARS-CoV-2 infection. In multivariate analysis, advanced age was an independent risk factor for death. Recent studies suggest a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome activation in lung inflammation and fibrosis in SARS-CoV and SARS-CoV-2 infections. Increased NLRP3/ apoptosis-associated speck-like protein (ASC) mRNA expression and increased caspase-1 activity, have been observed in aged lung, provoking increased and heightened expression levels of mature Interleukin (IL)-1β and IL-18 in aged individuals. Aged individuals have a basal predisposition to over-react to infection, displaying an increased hyper-inflammatory cascade, that seems not to be fully physiologically controlled. NLRP3 inflammasome is over-activated in aged individuals, through deficient mitochondrial functioning, increased mitochondrial Reactive Oxigen Species (mtROS) and/or mitochondrial (mt)DNA, leading to a hyper-response of classically activated macrophages and subsequent increases in IL-1 β. This NLRP3 over-activated status in elderly individuals, is also observed in telomere dysfunctional mice models. In our opinion, the NLRP3 inflammasome plays a central role in the increased lethality observed in elderly patients infected by COVID-19. Strategies blocking inflammasome would deserve to be studied.

Keywords NLRP3      inflammasome      age      COVID-19      pneumonia     
Corresponding Authors: Lara Pedro C   
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These authors contributed equally to this work.

Just Accepted Date: 14 June 2020   Issue Date: 30 July 2020
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Lara Pedro C
Macías-Verde David
Burgos-Burgos Javier
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Lara Pedro C,Macías-Verde David,Burgos-Burgos Javier. Age-induced NLRP3 Inflammasome Over-activation Increases Lethality of SARS-CoV-2 Pneumonia in Elderly Patients[J]. Aging and disease, 2020, 11(4): 756-762.
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[1] Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z et al (2020). Clinical Course and Risk Factors for Mortality of Adult Inpatients With COVID-19 in Wuhan, China: A Retrospective Cohort Study Lancet, 395(10229):1054-1062
[2] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ et al (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet, 395(10229):1033-103
[3] McGonagle D, Sharif K, O'Regan A, Bridgewood C (2020). Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome. Autoimmun Rev,3:102537
[4] Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L et al (2020). Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney International, 5:829-838
[5] Madsbad S (2020). COVID-19 Infection in People with Diabetes. Touch Endocrinology (in press)
[6] Siddiqi HK & Mehra MR (2020). COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. The Journal of Heart and Lung Transplantation, in press
[7] Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, et al (2007). IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest,117:3786-3799
[8] Shi CS, Nabar NR, Huang NN, Kehrl JH (2019) SARS-Coronavirus Open Reading Frame-8b Triggers Intracellular Stress Pathways and Activates NLRP3 Inflammasomes. Cell Death Discov,5:101.
[9] Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I, et al (2020). Induction of Pro-Inflammatory Cytokines (IL-1 and IL-6) and Lung Inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-Inflammatory Strategies. J Biol Regul Homeost Agents, 14;34(2):1
[10] Swanson KV, Meng D, Ting JP-Y(2019). The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology, 19:477-489.
[11] Pirzada RH, Javaid N, Choi S (2020). The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions Genes, 11(2) pii: E131.
[12] Yang Y, Wang H, Kouadir M, Song H, Shi F(2019). Recent advances in the mechanisms of NLRP3 inflammasome activation and its Inhibitors. Cell Death and Disease, 10:128.
[13] Kelley N, Jeltema D, Duan Y, He Y (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci, 20(13): 3328.
[14] Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, et al (2015). Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology, 485:330-9.
[15] Chang YS, Ko BH, Ju JC, Chang HH, Huang SH, Lin CW (2020) SARS Unique Domain (SUD) of Severe Acute Respiratory Syndrome Coronavirus Induces NLRP3 Inflammasome-Dependent CXCL10-Mediated Pulmonary Inflammation. Int J Mol Sci, 21(9), pii: E3179.
[16] Guo S, Yang C, Diao B, Huang X, Jin M, Chen L, et al (2015). The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis. PLoS Pathog, 11(9):e1005155
[17] Yue Y, Nabar NR, Shi C, Kamenyeva O, Xiao X, Hwang IY, et al (2018). SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death. Cell Death Dis, 9(9):904
[18] Chen IY, Moriyama M, Chang MF, Ichinohe T (2019). Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome. Front Microbiol,10:50.
[19] Siu KL, Yuen KS, Castaño-Rodriguez C (2019). Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J, 33(8):8865-8877
[20] Xu J, Zhao S, Teng T (2020). Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses, 12(2):244
[21] Cagliani R, Forni D, Clerici M, Sironi M (2020). Computational inference of selection underlying the evolution of the novel coronavirus SARS-CoV-2. J Virol, in press
[22] Choi KW, Chau TN, Tsang O, Tso E, Chiu MC, Tong WL, et al (2003). Outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in Hong Kong. Ann Intern Med, 139: 715-23.
[23] Hong KH, Choi JP, Hong SH, Lee J, Kwon JS, Kim SM, et al (2018). Predictors of mortality in Middle East respiratory syndrome (MERS). Thorax, 73: 286-89.
[24] Navaratnam V, Fleming KM, West J, Smith CJP, Jenkins RG, Fogarty A, et al (2011). The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax, 66:462-467.
[25] Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T, et al (2006) A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit Care Med, 173:781-792.
[26] Stout-Delgado HW, Cho SJ, Chu SG, Mitzel N, Villalba J, El-Chemaly S, et al (2016). Age-Dependent Susceptibility to Pulmonary Fibrosis Is Associated With NLRP3 Inflammasome Activation Am J Respir Cell Mol Biol, 55(2):252-63.
[27] Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, et al (2005). Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science, 309:481-484.
[28] Lee HC, Wei YH (2012). Mitochondria and aging. Adv Exp Med Biol, 942:311-327.
[29] Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, et al (2012). Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature, 485: 251-255.
[30] Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Tolinay T, Lam HC, et al (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol, 12:222-230.
[31] Howcroft TK, Campisi J, Louis GB, Smith MT, Wise B, Wyss-Coray T, et al (2013). The role of inflammation in age-related disease. Aging, 5:84-93.
[32] Brar SS, Meyer JN, Bortner CD, Van Houten B, Martin WJ (2012). Mitochondrial DNA-depleted A549 cells are resistant to bleomycin. Am J Physiol Lung Cell Mol Physiol, 303:413-424.
[33] Mitroulis I, Skendros P, Ritis K (2010). Targeting IL-1β in disease; the expanding role of NLRP3 inflammasome. Eur J Intern Med, 21:157-163
[34] Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, et al (2007). Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med, 13: 742-747.
[35] Sahin E, Colla S, Liesa M, Guo M, Cooper M, Kotton D, Fabian AJ, et al (2011). Telomere dysfunction induces metabolic and mitochondrial compromise. Nature, 470(7334):359-65
[36] Kang Y, Zhang H, Zhao Y, Wang Y, Wang W, He Y et al (2018). Telomere Dysfunction Disturbs Macrophage Mitochondrial Metabolism and the NLRP3 Inflammasome Through the PGC-1α/TNFAIP3 Axis. Cell Rep, 22(13):3493-3506.
[37] Dinarello CA, van der Meer JWM (2013). Treating Inflammation by Blocking interleukin-1 in Humans. Semin Immunol, 25(6):469-84.
[38] Guo H, Callaway JB, Ting JP (2015). Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med, 21: 677-687.
[39] Canan CH, Gokhale NS, Carruthers B, Lafuse WP, Schlesinger LS, Torrelles JB, et al (2014). Characterization of lung inflammation and its impact on macrophage function in aging. J Leukoc Biol, 96(3): 473-480.
[40] Imai Y, Kuba K, Neely GG (2008). Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell, 133: 235-249.
[41] Smits SL, de Lang A, van den Brand JMA, Leijten LM, van IJcken WF, Eijkemans MJC, et al (2010). Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathog, 6: e1000756-e.
[42] Chung HY, Sung B, Jung KJ, Zou Y, Byung Pal Yu BP (2006). The Molecular Inflammatory Process in Aging Antioxid Redox Signal, 8(3-4):572-81
[43] Yu P, Qi F, Xu Y, Li F, Liu P, Liu J, et al (2020). Age-related Rhesus Macaque Models of COVID-19. Animal Model Exp Med, 3(1):93-97.
[44] Opal SM, Girard TD, Ely EW (2005). The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis, 41(7): S504-12
[45] Li W, Shi Z, Yu M (2005). Bats are natural reservoirs of SARS-like coronaviruses. Science, 310: 676-679.
[46] Wilkinson GS & South JM (2002). Life history, ecology and longevity in bats. Aging Cell, 1:124-131
[47] Ahn M, Anderson DE, Zhang Q, Tan CW, Lim BL, Luko K, et al (2019). Dampened NLRP3-mediated Inflammation in Bats and Implications for a Special Viral Reservoir Host. Nat Microbiol, 4(5):789-799.
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