期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 9, 页码 1655-1662出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160061
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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.
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