Interferon Regulatory Factor 5 represses oxidative respiration in human and murine macrophages by inhibition of mitochondrial matrix protein GHITM

Abstract Over the course of diet-induced obesity (DIO), adipose tissue macrophage (ATM) populations transition from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that the Interferon Regulatory Factor (IRF)-5 is a key molecular switch mediating repression of macrophage oxidative capacity early in DIO. ATMs from mice with a myeloid-specific deletion of IRF5 are characterised by increased mitochondrial activity and oxidative respiration compared to ATMs from wild-type mice. This hyper-oxidative phenotype is inducible and reversible in vitro by delivery of an inhibitory IRF5-decoy peptide and through IRF5 adenoviral over-expression, respectively. In a data-driven approach, using public IRF5-cistrome data and in-house RNA-sequencing, we identified a transcriptional mechanism by which cellular oxidative capacity is repressed in an IRF5-dependent manner. The hyper-oxidative phenotype of IRF5-deficient macrophages is mediated by the Growth Hormone Inducible Transmembrane Protein (GHITM), known for maintaining mitochondrial architecture for optimal oxidative respiration. Cas9-mediated simultaneous knock-down of GHITM and of IRF5 reverses the hyper-oxidative phenotype associated with IRF5-deficiency in vitro. IRF5-dependent regulation of GHITM expression and mitochondrial activity extends to human ATMs and monocytes from obese and diabetic patients.