Succinate receptor deficiency attenuates arthritis by reducing dendritic cell traffic and expansion of T_h17 cells in the lymph nodes

Rheumatoid arthritis is a chronic inflammatory disease that leads to significant changes in metabolic activity. Succinate, an intermediate of the tricarboxylic acid cycle, has emerged as a metabolic mediator of the innate immune response. However, the involvement of succinate in the generation of the adaptive immune response and establishment of autoimmune response has not been addressed thus far. Here we demonstrated that the succinate-sensing receptor (Sucnr1/GPR91) plays a critical role in the development of immune-mediated arthritis. We found that Sucnr1 acts as a chemotactic gradient sensor that guides dendritic cells (DCs) into the lymph nodes, orchestrating the expansion of the T helper (T_h)17-cell population and the development of experimental antigen-induced arthritis. Sucnr1^-/- mice show reduced articular hyperalgesia, neutrophil infiltration and inflammatory cytokines in the joint, and reduced frequency of T_h17 cells in draining lymph nodes. Adoptive transfer of wild-type (WT) DCs into Sucnr1^-/- mice restored the development of arthritis. Moreover, DC-depleted mice transferred with Sucnr1^-/- DCs developed less arthritis than mice transferred with WT DCs. In contrast, succinate given together with the immunization boosted the recruitment of DCs and the frequency of T_h17 cells in draining lymph nodes, increasing arthritis severity. Therefore, the blockade of Sucnr1 may represent a novel therapeutic target of arthritis.-Saraiva, A. L., Veras, F. P., Peres, R. S., Talbot, J., de Lima, K. A., Luiz, J. P., Carballido, J. M., Cunha, T. M., Cunha, F. Q., Ryffel, B., Alves-Filho, J. C. Succinate receptor deficiency attenuates arthritis by reducing dendritic cell traffic and expansion of T_h17 cells in the lymph nodes.