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

David Furman, Junlei Chang, Lydia Lartigue, Christopher R Bolen, François Haddad, Brice Gaudilliere, Edward A Ganio, Gabriela K Fragiadakis, Matthew H Spitzer, Isabelle Douchet, Sophie Daburon, Jean-François Moreau, Garry P Nolan, Patrick Blanco, Julie Déchanet-Merville, Cornelia L Dekker, Vladimir Jojic, Calvin J Kuo, Mark M Davis, Benjamin Faustin

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 N(4)-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.