Abstract

Macrophage effector function is dynamic in nature and largely dependent upon not only the type of immunological challenge, but also the tissue-specific environment and developmental origin of a given macrophage population. Recent research has highlighted the importance of glycolytic metabolism in the regulation of effector function as a common feature associated with macrophage activation. Yet, most research has utilized macrophage cell lines and bone marrow-derived macrophages (BMDMs), which do not account for the diversity of macrophage populations and the role of tissue specificity in macrophage immunometabolism. Tissue-resident alveolar macrophages (TR-AMs) reside in an environment characterized by remarkably low glucose concentrations, making glycolysis-linked immunometabolism an inefficient and unlikely means for immune activation. In this study, we show that TR-AMs rely on oxidative phosphorylation to meet their energy demands and maintain extremely low levels of glycolysis under steady-state conditions. Unlike BMDMs, TR-AMs do not experience enhanced glycolysis in response to lipopolysaccharide (LPS), and glycolytic inhibition had no effect on their proinflammatory cytokine production. HIF-1α stabilization promoted glycolysis in TR-AMs and shifted energy production away from oxidative metabolism at baseline, but it was not sufficient for TR-AMs to mount further increases in glycolysis or enhance immune function in response to LPS. Importantly, we confirmed these findings in an in vivo influenza model where infiltrating macrophages had significantly higher glycolytic and proinflammatory gene expression compared to TR-AMs. These findings demonstrate that glycolysis is dispensable for macrophage effector function in TR-AMs, and highlight the importance of macrophage tissue origin (tissue resident vs. recruited) in immunometabolism.