GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis

被引：421

作者：

Littlewood-Evans, Amanda ^{[1
]}

Sarret, Sophie ^{[1
]}

Apfel, Verena ^{[1
]}

Loesle, Perrine ^{[1
]}

Dawson, Janet ^{[1
]}

Zhang, Juan ^{[3
]}

Muller, Alban ^{[3
]}

Tigani, Bruno ^{[4
]}

Kneuer, Rainer ^{[4
]}

Patel, Saijel ^{[1
]}

Valeaux, Stephanie ^{[1
]}

Gommermann, Nina ^{[5
]}

Rubic-Schneider, Tina ^{[2
]}

Junt, Tobias ^{[1
]}

Carballido, Jose M. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Dept Autoimmun Transplantat & Inflammat, CH-4002 Basel, Switzerland

[2] Novartis Inst BioMed Res, Preclin Safety Div, CH-4002 Basel, Switzerland

[3] Novartis Inst BioMed Res, Dept Analyt Sci & Imaging, CH-4002 Basel, Switzerland

[4] Novartis Inst BioMed Res, Global Imaging Grp, CH-4002 Basel, Switzerland

[5] Novartis Inst BioMed Res, Global Discovery Chem, CH-4002 Basel, Switzerland

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2016年 / 213卷 / 09期

关键词：

RECEPTOR GPR91; ACTIVATION; POLARIZATION; EXPRESSION; IL-1-BETA; BIOMARKER; SIGNAL; CELLS; ACID; GENE;

D O I：

10.1084/jem.20160061

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate. In this study, we show that during this activation, macrophages release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1 beta production. GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1 beta during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1 beta release from macrophages in a GPR91-dependent manner. Together, we reveal a GPR91/succinate-dependent feed-forward loop of macrophage activation and propose GPR91 antagonists as novel therapeutic principles to treat RA.

引用

页码：1655 / 1662

页数：8

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