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Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states

Abstract

Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N4-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.

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Figure 1: Expression of inflammasome gene modules in older adults and its association with human health and longevity.
Figure 2: Metabolites present in IMH individuals induce IL-1β and upregulate the expression of inflammasome genes.
Figure 3: Metabolites in IMH individuals activate the NLRC4 inflammasome.
Figure 4: Metabolites in IMH individuals activate human primary platelets and neutrophils.
Figure 5: Metabolites in IMH individuals induce high blood pressure in mice.
Figure 6: Caffeine negatively regulates the NLRC4 inflammasome.

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Acknowledgements

We thank the Stanford–Ellison longitudinal cohort volunteers for their participation; Project/Regulatory/Data Manager S. Mackey; Research Nurses S. Swope, C. Walsh, S. French, B. Sullivan, S. Cathey, T. Trela and N. Mastman; Clinical Research Associates A. Goel, T. Quan, K. Span, R. Fleischmann, B. Tse, I. Chang and S. Batra. We also are grateful to The Ellison Medical Foundation for initial support and to the NIH (U19 AI090019) and the Howard Hughes Medical Institute for the remainder (M.M.D.). We also thank H. Maecker and Y. Rosenberg-Hasson (Human Immune Monitoring Core) at Stanford, and R.E. Vance and I. Rauch at the University of California, Berkeley, for kindly providing us with material from NLRC4 and caspase-1 knockout mice. B.F., J.D-M. and J.F.M. were funded by Fondation pour la Recherche Médicale (DEQ20110421287), INCa-Cancéropôle GSO, Ligue contre le Cancer de la Dordogne, and the Conseil Régional d'Aquitaine. We thank the Metabolon Inc. for the metabolite analysis.

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Contributions

Gene expression data were generated at the Human Immune Monitoring Core (Stanford University). D.F. and B.F. conducted stimulation, inhibition and qPCR assays; D.F., C.R.B. and V.J. analyzed data; D.F., B.F., S.D., L.L., I.D. and P.B, designed or conducted in vitro studies of monocyte and platelet activation; J.C. and C.J.K. helped with the design and conducted the hypertension studies in mice; D.F., B.G., E.A.G., G.P.N., G.K.F. and M.H.S. designed or conducted the mass cytometry studies F.H. supervised cardiovascular phenotyping data generation; J.-F.M. and J.D.-M. helped with clinical insights and discussion; C.L.D. coordinated, organized and conducted the clinical studies and contributed to study design; G.P.N. and M.M.D. provided support, contributed with the planning of the immunological studies and contributed to study design; D.F., M.M.D. and B.F. wrote the manuscript.

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Correspondence to David Furman, Mark M Davis or Benjamin Faustin.

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Furman, D., Chang, J., Lartigue, L. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 23, 174–184 (2017). https://doi.org/10.1038/nm.4267

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