Triggering the succinate receptor GPR91 on dendritic cells enhances immunity.
Succinate acts as an extracellular mediator signaling through the G protein-coupled receptor GPR91. Here we show that dendritic cells had high expression of GPR91. In these cells, succinate triggered intracellular calcium mobilization, induced migratory responses and acted in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines. Succinate also enhanced antigen-specific activation of human and mouse helper T cells. GPR91-deficient mice had less migration of Langerhans cells to draining lymph nodes and impaired tetanus toxoid-specific recall T cell responses. Furthermore, GPR91-deficient allografts elicited weaker transplant rejection than did the corresponding grafts from wild-type mice. Our results suggest that the succinate receptor GPR91 is involved in sensing immunological danger, which establishes a link between immunity and a metabolite of cellular respiration.
Rubic
Tina
T
Novartis Institutes for Biomedical Research, Vienna A-1235, Austria.
Lametschwandtner
Günther
G
Jost
Sandra
S
Hinteregger
Sonja
S
Kund
Julia
J
Carballido-Perrig
Nicole
N
Schwärzler
Christoph
C
Junt
Tobias
T
Voshol
Hans
H
Meingassner
Josef G
JG
Mao
Xiaohong
X
Werner
Gudrun
G
Rot
Antal
A
Carballido
José M
JM
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D019802:Succinic Acid / Q000378:metabolism* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; C531499:GPR91 protein, mouse; D011948:Receptors, Antigen, T-Cell; D043562:Receptors, G-Protein-Coupled; D019802:Succinic Acid