Dawson King, Janet (2016) GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. no journal (9).

Abstract

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-1beta production. GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1beta during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1beta 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
Additional Information:	Unmapped bibliographic data: LA - eng [Field not mapped to EPrints] ET - 2016/08/03 [Field not mapped to EPrints] ST - GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis [Field not mapped to EPrints] AU - Littlewood-Evans, A. [Field not mapped to EPrints] AU - Sarret, S. [Field not mapped to EPrints] AU - Apfel, V. [Field not mapped to EPrints] AU - Loesle, P. [Field not mapped to EPrints] AU - Dawson, J. [Field not mapped to EPrints] AU - Zhang, J. [Field not mapped to EPrints] AU - Muller, A. [Field not mapped to EPrints] AU - Tigani, B. [Field not mapped to EPrints] AU - Kneuer, R. [Field not mapped to EPrints] AU - Patel, S. [Field not mapped to EPrints] AU - Valeaux, S. [Field not mapped to EPrints] AU - Gommermann, N. [Field not mapped to EPrints] AU - Rubic-Schneider, T. [Field not mapped to EPrints] AU - Junt, T. [Field not mapped to EPrints] AU - Carballido, J. M. [Field not mapped to EPrints] C2 - PMC4995082 [Field not mapped to EPrints] AD - Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland amanda.littlewood-evans@novartis.com. [Field not mapped to EPrints] DP - NLM [Field not mapped to EPrints] AN - 27481132 [Field not mapped to EPrints]
Keywords:	Inflammation, arthritis, GPR4, GPR91
Date Deposited:	13 Dec 2016 00:45
Last Modified:	13 Dec 2016 00:45
URI:	https://oak.novartis.com/id/eprint/31752