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GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2016 Aug 22; Vol. 213 (9), pp. 1655-62. Date of Electronic Publication: 2016 Aug 01. - Publication Year :
- 2016
-
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-1β production. GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1β during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1β 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.<br /> (© 2016 Littlewood-Evans et al.)
- Subjects :
- Animals
Arthritis, Rheumatoid metabolism
Female
Humans
Interleukin-1beta metabolism
Lipopolysaccharides pharmacology
Mice
Mice, Inbred C57BL
Receptors, G-Protein-Coupled antagonists & inhibitors
U937 Cells
Arthritis, Rheumatoid etiology
Macrophages metabolism
Receptors, G-Protein-Coupled physiology
Succinic Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 213
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27481132
- Full Text :
- https://doi.org/10.1084/jem.20160061