GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis

We show that during this activation, macrophages release succinate into the extracellular milieu

Amanda Littlewood-Evans; Sophie Sarret; Verena Apfel; Perrine Loesle; Janet Dawson; Juan Zhang; Alban Muller; Bruno Tigani; Rainer Kneuer; Saijel Patel; Stephanie Valeaux; Nina Gommermann; Tina Rubic-Schneider; Tobias Junt; José M. Carballido


Scholarcy highlights

  • Macrophages switch their metabolism from oxidative phosphorylation to glycolysis in the presence of oxygen after activation with inflammatory triggers such as TLR-2, -3, -4, and -9
  • Sucnr1 expression mediated by IL-1β but not by LPS was reduced by inhibitors of IκB and p38 kinases, implying a direct effect of this cytokine and of additional TLR4driven mediators in the induction of GPR91
  • This effect was independent of GPR91 expression, and strikingly, extracellular succinate was found more abundantly in cultures of Sucnr1−/− BMDMs than in corresponding WT cells
  • Succinate release appears to be a specific function of activated macrophages rather than the consequence of macrophage death, as we observed no differences in lactate dehydrogenase release or expression of cell death markers upon LPS stimulation
  • We observed that LPS-activated BMDMs from Sucnr1−/− mice showed a profound decrease of IL-1β release, IL-1β mRNA, and pro–IL-1β production compared with their WT controls
  • We found that Sucnr1−/− inflammatory macrophages were deficient in their IL-1β release upon activation with the classical inflammasome stimulus LPS/monosodium urate
  • This mechanism fuels inflammation in an autocrine manner and propagates inflammation by alerting neighboring cells of the immunological danger.GPR91-driven recycling of extracellular succinate by macrophages is one example of how the immune system utilizes excess metabolites that are not used for its primary purpose, the generation of metabolic energy

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