Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging

被引：527

作者：

Youm, Yun-Hee ^{[1
]}

Grant, Ryan W. ^{[1
]}

McCabe, Laura R. ^{[2
]}

Albarado, Diana C. ^{[1
]}

Nguyen, Kim Yen ^{[1
]}

Ravussin, Anthony ^{[1
]}

Pistell, Paul ^{[1
]}

Newman, Susan ^{[1
]}

Carter, Renee ^{[3
]}

Laque, Amanda ^{[1
]}

Muenzberg, Heike ^{[1
]}

Rosen, Clifford J. ^{[4
]}

Ingram, Donald K. ^{[1
]}

Salbaum, J. Michael ^{[1
]}

Dixit, Vishwa Deep ^{[1
,5
,6
]}

机构：

[1] LSU Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA

[2] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA

[3] Louisiana State Univ, Sch Vet Med, Dept Vet Clin Sci, Baton Rouge, LA 70803 USA

[4] Maine Med Ctr, Res Inst, Ctr Clin & Translat Res, Scarborough, ME 04074 USA

[5] Yale Univ, Sch Med, Sect Comparat Med, New Haven, CT 06520 USA

[6] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

来源：

CELL METABOLISM | 2013年 / 18卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ADIPOSE-TISSUE; URIC-ACID; ACTIVATION; OBESITY; DIET; PERSPECTIVE; CASPASE-1; PROTECTS; HEALTH; CELLS;

D O I：

10.1016/j.cmet.2013.09.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related "sterile'' inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.

引用

页码：519 / 532

页数：14

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