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.

BackgroundSuccinate, in addition to its role as an intermediary of the citric acid cycle, acts as an alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution of this immune sensing pathway to the development of allergic and inflammatory responses is unknown.MethodsEar thickness of wild‐type (wt) and Sucnr1‐deficient (Sucnr1 −/−) mice, sensitized and challenged with oxazolone, was used as a criterion to assess the relevance of SUCNR1/GPR91 expression mediating allergic contact dermatitis (ACD). Results obtained in this system were contrasted with data generated using passive cutaneous anaphylaxis, ovalbumin‐induced asthma and arthritis models.ResultsWe found augmented ACD reactions in Sucnr1 −/− mice. This observation correlated with increased mast cell activation in vitro and in vivo. However, exacerbated mast cell activation in Sucnr1 −/− mice did not contribute to the enhancement of asthma or arthritis and seemed to be due to alterations during mast cell development as augmented mast cell responses could be recapitulated in wt mast cells differentiated in the absence of succinate.ConclusionsA deficiency in succinate sensing during mast cell development confers these cells with a hyperactive phenotype. Such a phenomenon does not translate into exacerbation of asthma or mast cell‐dependent arthritis. On the contrary, the fact that Sucnr1 −/− mice developed reduced arthritic disease, using two different in vivo models, indicates that GPR91 antagonists may have therapeutic potential for the treatment of allergic and autoimmune diseases.