Trained immunity of alveolar macrophages depends on metabolic rewiring and type 1 interferon signaling (ATAC-Seq)

Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We showed that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) protected mice from bacterial pneumonia six days later and discovered a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that trained AMs displayed a substantially modulated metabolite and lipid composition. Inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect, suggesting a key function of metabolic rewiring in LPS-induced AM memory. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and highlight tissue-specific features of trained immunity. ATAC-seq analysis of trained and control AMs: Wild type mice received LPS (Sigma; E.coli O55:B5) or endotoxin-free saline intranasally (i.n.). Six days later, LPS-exposed ("trained") and saline-exposed ("control") AMs were isolated by broncho-alveolar lavage from biological replicates (ctrl:n=4; LPS:n=5) and counted. For each biological replicate, 50.000 cells were pelleted and processed for ATAC-seq analysis.