IRF5 regulates airway macrophage metabolic responses

Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage phenotype and a key transcription factor involved in expression of proinflammatory cytokine responses to microbial and viral infection. Here, we show that IRF5 controls cellular and metabolic responses. By integrating ChIP sequencing (ChIP‐Seq) and assay for transposase‐accessible chromatin using sequencing (ATAC)‐seq data sets, we found that IRF5 directly regulates metabolic genes such as hexokinase‐2 (Hk2). The interaction of IRF5 and metabolic genes had a functional consequence, as Irf5(−/−) airway macrophages but not bone marrow‐derived macrophages (BMDMs) were characterized by a quiescent metabolic phenotype at baseline and had reduced ability to utilize oxidative phosphorylation after Toll‐like receptor (TLR)‐3 activation, in comparison to controls, ex vivo. In a murine model of influenza infection, IRF5 deficiency had no effect on viral load in comparison to wild‐type controls but controlled metabolic responses to viral infection, as IRF5 deficiency led to reduced expression of Sirt6 and Hk2. Together, our data indicate that IRF5 is a key component of AM metabolic responses following influenza infection and TLR‐3 activation.