GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury

Area of Science:

• Immunometabolism
• Respiratory Medicine
• Cellular Biology

Background:

• Acute respiratory distress syndrome (ARDS) is linked to impaired macrophage efferocytosis and poor clinical outcomes associated with hyperlactatemia.
• The immunometabolic role of lactate in ARDS pathogenesis remains incompletely understood.

Purpose of the Study:

• To investigate the impact of lactate on macrophage function and inflammation resolution in ARDS.
• To elucidate the mechanisms by which lactate affects efferocytosis and lung injury.

Main Methods:

• LPS-induced ARDS mouse model treated with exogenous lactate or lactate dehydrogenase inhibitor.
• Flow cytometry and H&E staining for inflammatory cell infiltration.
• In vitro studies using primary Alveolar Macrophages (AMs) to assess efferocytosis and gene/protein expression (Glut1, MCT1, GPR81, Myc).
• GPR81-deficient mice and siRNA-mediated Myc silencing were utilized.

Main Results:

• Exogenous lactate exacerbated lung injury and delayed inflammation resolution in the ARDS model.
• GPR81 deficiency reduced neutrophil infiltration and improved outcomes.
• Lactate accumulation by macrophages during efferocytosis upregulated Glut1, MCT1, and GPR81.
• Pharmacological inhibition of LDH or MCT1, or excess lactate, impaired efferocytosis.
• Exogenous lactate suppressed Myc upregulation, while GPR81 ablation increased MCT1 and Myc expression. Myc silencing impaired efferocytosis.

Conclusions:

• Lactate, via GPR81 activation, delays inflammation resolution in acute lung injury.
• This delay is mediated by suppressed alveolar macrophage efferocytosis, hindering apoptotic cell clearance and worsening lung injury.
• Targeting lactate metabolism and signaling pathways presents a potential therapeutic strategy for ARDS.