Lactic acid suppresses LPS-induced cytokine production in vitro and in vivo.

Abstract

Abstract Sepsis is a considerable health burden worldwide with no molecular-based drug treatments. Following the cytokine storm, a hypoinflammatory phase is observed in patients, characterized by impaired cytokine production and glycolysis in immune cells. Lactic acid levels are associated with mortality in patients; however, any regulatory role of lactic acid is currently unknown. We hypothesized that lactic acid contributes to the late phase of sepsis and is not solely a consequence of bacterial infection. As a product of glycolysis, lactic acid may feedback to inhibit glycolysis and overall energy production. Therefore, our purpose was to examine the effects of lactic acid on LPS-induced cytokine production and glycolysis in vitro and on LPS-induced septic shock in vivo. In bone marrow derived and peritoneal mast cells, lactic acid significantly suppressed cytokine and chemokine production at concentrations ≥ 6mM (IL-6) and 12.5 mM (TNF and MCP-1). These effects were dependent upon pH and MCT-1 transport. Additionally, lactic acid attenuated glucose uptake, lactate production, and the expression of the glycolytic enzyme hexokinase 2 following LPS-activation. Extending our in vitro results, lactic acid significantly suppressed IL-6, TNF-α, and MCP-1 induction in multiple in vivo experiments using LPS-induced septic shock. Interestingly, lactic acid did not affect temperature change or observational score. These findings suggest that elevated lactic acid levels may contribute to reduced cytokine concentrations and impaired immune cell metabolism observed in sepsis patients. This information may improve our understanding of immunosuppression in the late phase of sepsis and could reveal new molecular targets for treatment.