Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability

Area of Science:

• Immunology
• Biochemistry
• Pathophysiology

Background:

• Sepsis involves an inflammatory phase and a poorly understood immunosuppressive phase.
• Elevated blood lactate and slow lactate clearance correlate with sepsis mortality, but their regulatory roles are unclear.
• Lactic acid (LA) is hypothesized to contribute to sepsis's late immunosuppressive phase, independent of bacterial infection.

Purpose of the Study:

• To investigate the regulatory role of lactic acid (LA) in the immunosuppressive phase of sepsis.
• To examine the effects of LA on mast cell activation and cytokine production in response to lipopolysaccharide (LPS).
• To elucidate the underlying mechanisms of LA-mediated immune suppression, focusing on glucose metabolism.

Main Methods:

• In vitro studies using mouse bone marrow-derived mast cells and peritoneal mast cells exposed to LPS and LA.
• In vivo studies using a mouse model of LPS-induced endotoxemia.
• Analysis of NF-κB transcriptional activity, cytokine production, glucose uptake, and lactate export.
• Investigation of the role of MCT-1 transporter and ATP availability.

Main Results:

• LA significantly suppressed LPS-induced cytokine production and NF-κB activity in mast cells.
• LA suppressed cytokine induction in mice with LPS-induced endotoxemia.
• LA reduced glucose uptake and lactate export during LPS stimulation, indicating glycolytic suppression.
• LA's effects were dependent on MCT-1 transporter and mimicked by glycolytic inhibitors, requiring sufficient ATP production.

Conclusions:

• Lactic acid plays a significant role in suppressing immune cell function during the immunosuppressive phase of sepsis.
• LA-induced immune suppression is mediated by the inhibition of glycolysis and subsequent reduction in ATP production.
• Strategies to enhance glycolysis and ATP production could be therapeutic for counteracting sepsis-induced immunosuppression.