GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury

Acute respiratory distress syndrome (ARDS) involves impaired macrophage function in clearing apoptotic cells. The link between clinical hyperlactatemia in ARDS patients and poor outcomes prompted this study on the immunometabolic role of lactate in disease progression. In an LPS-induced ARDS mouse model, mice received either exogenous lactate or a lactate dehydrogenase inhibitor. Inflammatory cell infiltration was evaluated through flow cytometry and histological analysis with hematoxylin and eosin staining. Lactate signaling was confirmed in GPR81-deficient mice. In vitro, lactate metabolism during efferocytosis was studied using primary Alveolar Macrophages (AMs). Lactate accumulation, neutrophil infiltration, and elevated inflammatory factors were observed in this ARDS model. External lactate delayed inflammation resolution and worsened lung injury. GPR81^-/- mice exhibited reduced neutrophil infiltration and better outcomes. Macrophages produced substantial amounts of lactate during efferocytosis in vitro, concurrent with upregulated expression of the glucose transporter Glut1, the lactate transporter MCT1, and the lactate receptor GPR81. Pharmacological inhibition using an LDH inhibitor, an MCT1 antagonist, or extra lactate significantly impaired efferocytic capacity. Efferocytosis triggered Myc upregulation in vitro, which was suppressed by exogenous lactate. Genetic ablation of GPR81 elevated both MCT1 and Myc expression. Silencing Myc via siRNA significantly impaired efferocytosis in vitro. These findings indicate that the activation of GPR81 by lactate delays the resolution of inflammation in acute lung injury. This effect may be attributed to the suppression of alveolar macrophage efferocytosis, which subsequently impairs the clearance of apoptotic cells and exacerbates lung injury.