Lactic acid suppresses LPS-induced mast cell cytokine production by limiting glycolysis and ATP availability

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Abstract Sepsis, a life threatening response to infection, has a well-studied initial cytokine storm, with a less understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality, however, any regulatory role is unknown. We hypothesized that lactic acid contributes to the late phase of sepsis and is not solely a consequence of bacterial infection. Thus far, no studies have examined the effect of lactic acid on sepsis models in vivo or a mechanism by which they suppress LPS activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined lactic acid effects on the mast cell response to the bacterial product LPS. Lactic acid significantly suppressed LPS-induced cytokine production and NFκB-mediated transcription in mouse bone marrow derived mast cells and cytokine production in peritoneal mast cells. Suppressive effects were MCT-1-dependent and observed with sodium lactate or formic acid. Further, lactic acid significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and lactic acid is a by-product of this process, we examined changes in glucose metabolism. Lactic acid treatment reduced glucose uptake and lactate export during LPS stimulation. Lactic acid effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for lactic acid effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting lactic acid suppressive effects in the immunosuppressive phase of sepsis.