title: GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis.
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.
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland amanda.littlewood-evans@novartis.com.
authors.forename: Amanda
authors.identifier: 0000-0001-7760-6535
authors.initials: A
authors.lastname: Littlewood-Evans
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Sophie
authors.identifier: 0000-0003-4470-669X
authors.initials: S
authors.lastname: Sarret
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Verena
authors.identifier: 0000-0002-2204-6822
authors.initials: V
authors.lastname: Apfel
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Perrine
authors.identifier: 0000-0001-8242-3100
authors.initials: P
authors.lastname: Loesle
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Janet
authors.identifier: 0000-0003-4615-4091
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Department of Analytical Science and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Analytical Science and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Alban
authors.identifier: 0000-0002-8474-5354
authors.initials: A
authors.lastname: Muller
authors.affiliation: Global Imaging Group, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Bruno
authors.identifier: 0000-0003-4640-584X
authors.initials: B
authors.lastname: Tigani
authors.affiliation: Global Imaging Group, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kneuer
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Saijel
authors.identifier: 0000-0002-9171-7431
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Stephanie
authors.identifier: 0000-0001-5575-7295
authors.initials: S
authors.lastname: Valeaux
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Nina
authors.identifier: 0000-0002-3684-4788
authors.initials: N
authors.lastname: Gommermann
authors.affiliation: Preclinical Safety Division, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Tina
authors.identifier: 0000-0001-6704-3783
authors.initials: T
authors.lastname: Rubic-Schneider
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Tobias
authors.identifier: 0000-0003-0260-8346
authors.initials: T
authors.lastname: Junt
authors.affiliation: Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: José M
authors.identifier: 0000-0001-8465-0665
authors.initials: JM
authors.lastname: Carballido
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D019802:Succinic Acid / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human; D019802:Succinic Acid