Irf5 Regulates Airway Macrophage Metabolic Responses To Viral Challenge

Background: Airway macrophages (AMs) are key sentinels of lung homeostasis and responses to inhaled allergens and pathogens. Recent work has shown that macrophage activation and plasticity are under metabolic control. Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the induction of pro-inflammatory cytokine responses to infection. Previous studies identified IRF5 as a master regulator of macrophage phenotype in vitro, however the role of IRF5 in directing AM metabolic responses to infection is not known. Aim: We hypothesise that IRF5 directs AM phenotype by metabolic reprogramming in response to infection. Methods: To investigate the role of IRF5 in the regulation of AM metabolism, disease pathology and inflammation, we infected WT and Irf5-/- mice with influenza. Moreover, bone marrow derived macrophages (BMDMs) and primary AMs were stimulated with TLR-agonists. To analyse the metabolic capacity of AMs, expression of pro-inflammatory/metabolic genes were assessed as well as the metabolic profile using an extracellular flux (Seahorse) assay. Results: Influenza-infected Irf5-/- mice had impaired myeloid cell responses in comparison to WT controls, characterised by decreased neutrophilia and increased eosinophilia. Analysis of IRF5 ChiP-Seq data and open chromatin regions (OCRs) revealed frequent binding of IRF5 to OCRs of pro-inflammatory mediator and metabolism genes. Moreover, Irf5-/- AMs but not BMDMs showed reduced mitochondrial oxygen consumption and extracellular acidification rate upon TLR3 stimulation or viral infection in comparison to WT controls. Conclusion: In summary, our data reveal a critical role of IRF5 in the regulation of AM metabolism in response to infection.