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Nat Med. 2017 Feb;23(2):174-184. doi: 10.1038/nm.4267. Epub 2017 Jan 16.

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

Author information

1
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.
2
Department of Systems Biology, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
3
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
4
INSERM U916 VINCO, Institut Bergonié, Bordeaux Cedex, France.
5
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
6
Institute of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
7
CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
8
Department of Pediatrics, Division of Infectious Diseases, Stanford University, Stanford, California, USA.
9
Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA.
10
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.

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.

PMID:
28092664
PMCID:
PMC5320935
DOI:
10.1038/nm.4267
[Indexed for MEDLINE]
Free PMC Article

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