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

Abstract

Abstract Despite a mortality rate of 30–50%, there are no targeted molecular treatments for sepsis. Our understanding of the secondary immunosuppressive phase is recent, and it is unclear whether many mediators are helpful or detrimental to patient survival. Elevated blood lactate and slow lactate clearance are associated with mortality, however, any regulatory roles are currently unknown. Because mast cells can be activated systemically and contribute to sepsis, this project aims to elucidate lactic acid effects on mast cell activation and signaling. Lactic acid significantly suppressed LPS-induced cytokine and chemokine production as well as NFκB transcription in bone marrow derived and peritoneal mast cells. These effects were dependent upon pH and MCT-1 transporter activity. Further, lactic acid significantly suppressed cytokine and chemokine induction following LPS-induced septic shock in vivo. We also examined the role of lactic acid as a feedback regulator of glucose metabolism. Lactic acid treatment reduced glucose uptake, lactate export, and hexokinase 2 expression following LPS activation. The glycolytic inhibitors 2-deoxyglucose, sodium oxamate, or dichloracetate mimicked lactic acid effects, suppressing LPS-induced cytokine production and NFκB transcription. Furthermore, adding ATP to the culture media at the time of LPS activation reversed lactic acid effects. These results indicate that suppressing glycolysis and ATP production are necessary and sufficient for lactic acid effects. Future studies should target enhancing glycolysis and ATP production to improve immune function and counteract lactic acid effects in sepsis.