Sucnr1 Mediates Leukocyte-Endothelial Cell Interactions Induced by Tnfα

Succinate is a metabolite involved in chronic inflammatory diseases, regulating macrophages, dendritic cells, and lymphocytes via its receptor SUCNR1 and through intracellular pathways. Our aim was to analyze whether the succinate-SUCNR1 axis modulates the leukocyte-endothelium interactions (L/EI) that mediate the formation of inflammatory foci in response to a ubiquitous pro-inflammatory cytokine (TNFα). L/EI were analyzed in murine cremasteric venules in vivo and between human umbilical endothelial cells (HUVECs) and peripheral blood mononuclear cells (PBMCs) in vitro. We observed that TNFα increased the expression of SUCNR1 and that the L/EI, the proinflammatory cytokines' upregulation and the NF-κB activation that induced this cytokine were reduced in Sucnr1^-/- mice in comparison with WT mice. Intrascrotal injection of exogenous succinate did not induce significant proinflammatory effects per se but, combined with TNFα, allowed a Sucnr1-independent upregulation of pro-inflammatory cytokines. In vitro, the SUCNR1 antagonist NF-56-EJ40 prevented the interactions of PBMCs with TNFα-treated HUVECs. HUVECs incubated with exogenous succinate presented higher L/EI but a limited response to TNFα. SUCNR1 contributes to TNFα-induced leukocyte-endothelial interactions. However, exogenous administration of high concentrations of this succinate exerts a complex pattern of effects that may include anti-inflammatory actions.