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GPR91 exacerbates rheumatoid arthritis via extracellular succinate released by intact inflammatory macrophages

Littlewood-Evans, Amanda and Sarret, Sophie and Apfel, Verena and Fuchs-Loesle, Perrine and Dawson King, Janet and Zhang, Juan and Muller, Alban and Tigani, Bruno and Kneuer, Rainer and Patel, Saijel and Gommermann, Nina and Rubic-Schneider, Tina and Junt, Tobias and Carballido, Jose and Valeaux, Stephanie (2016) GPR91 exacerbates rheumatoid arthritis via extracellular succinate released by intact inflammatory macrophages. Journal of Experimental Medicine.

Abstract

When SUCNR1/GPR91 expressing macrophages are activated by inflammatory signals they change their metabolism and accumulate succinate. Here we show that during this activation macrophages release succinate into the extracellular milieu. They simultaneously upregulate GPR91 which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1 production. GPR91 deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1 during antigen-induced arthritis (AIA). Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1 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.

Item Type: Article
Keywords: GPR91, succinate, rheumatoid arthritis, inflammation, macrophage
Date Deposited: 11 Jul 2016 23:45
Last Modified: 11 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/28000

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