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

被引：355

作者：

Furman, David ^{[1
,2
]}

Chang, Junlei ^{[3
]}

Lartigue, Lydia ^{[4
]}

Bolen, Christopher R. ^{[5
,11
]}

Haddad, Francois ^{[6
]}

Gaudilliere, Brice ^{[5
]}

Ganio, Edward A. ^{[5
]}

Fragiadakis, Gabriela K. ^{[5
]}

Spitzer, Matthew H. ^{[5
]}

Douchet, Isabelle ^{[7
]}

Daburon, Sophie ^{[7
]}

Moreau, Jean-Francois ^{[7
]}

Nolan, Garry P. ^{[5
]}

Blanco, Patrick ^{[7
]}

Dechanet-Merville, Julie ^{[7
]}

Dekker, Cornelia L. ^{[8
]}

Jojic, Vladimir ^{[9
]}

Kuo, Calvin J. ^{[3
]}

Davis, Mark M. ^{[1
,10
]}

Faustin, Benjamin ^{[7
]}

机构：

[1] Stanford Univ, Sch Med, Inst Transplantat Immunol & Infect, Stanford, CA 94305 USA

[2] Sidra Med & Res Ctr, Div Translat Med, Dept Syst Biol, Doha, Qatar

[3] Stanford Univ, Dept Med, Div Hematol, Sch Med, Stanford, CA 94305 USA

[4] INSERM U916 VINCO, Inst Bergonie, Bordeaux, France

[5] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Sch Med, Inst Cardiovasc Med, Stanford, CA 94305 USA

[7] Univ Bordeaux 2, UMR CNRS 5164, CIRID, Bordeaux, France

[8] Stanford Univ, Dept Pediat, Div Infect Dis, Stanford, CA 94305 USA

[9] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA

[10] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA

[11] Genentech Inc, Bioinformat Dept, San Francisco, CA 94080 USA

来源：

NATURE MEDICINE | 2017年 / 23卷 / 02期

关键词：

ESSENTIAL-HYPERTENSION; CARDIOVASCULAR-DISEASE; INTERLEUKIN-18; LEVELS; T-CELLS; ACTIVATION; RECEPTOR; PROTEINS; PATHWAY; AGE;

D O I：

10.1038/nm.4267

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-1 beta (IL-1 beta). Here we find that the expression of specific inflarnmasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1 beta, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of 1L-1 beta, 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-1 beta, 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.

引用

页码：174 / 184

页数：11

共 46 条

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