Lactate promotes IL-8 secretion in human alveolar macrophages through GPR132 and lipid metabolic reprogramming

Abstract

Alveolar macrophages are the primary lung immune cell. They play a crucial role in both maintenance of tissue homeostasis and the initiation of inflammation, secreting multiple immune mediators including the chemokine interleukin-8 (IL-8). Inflammatory settings are often characterised by tissue hypoxia, increased glycolytic rates and lactate secretion, yet how lactate influences alveolar macrophage function remains unclear. Here we investigated how lactate, once considered a waste-product, shapes alveolar macrophage function. To do so, primary human alveolar macrophages (hAMs) and a combination of flow cytometry, ELISA/Luminex, western blot, light microscopy, bioluminescence resonance energy transfer (BRET) and analysis of publicly available datasets were used to understand the role of lactate in lung pathological environments. We demonstrate that hAMs sense extracellular lactate via the expression of different lactate transporters (e.g. MCT1, MCT4) and receptors (i.e. GPR132). Lactate treatment of hAMs increased IL-8 secretion in a MCT1-dependent manner. Lipid metabolism and lipid droplet formation, as well as direct lactate-driven GPR132 signalling were required for lactate-dependent IL-8 release. Our findings uncover a previously unrecognised dual mechanism by which lactate orchestrates immune regulation in hAMs. Specifically, lactate-driven IL-8 production requires two distinct lactate-driven processes: uptake via MCT1, which reprograms lipid metabolism, and signaling through the lactate receptor GPR132. This functional integration of lactate transport and receptor-mediated signaling provides new mechanistic insight into lactates role in hAM biology and highlights potential targets for therapeutic intervention.