Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling

• DOI: 10.1038/s41467-022-32813-z
• Publication Date: 2022-08-30T06:04:46Z
• Authors: L. Orliaguet; T. Ejlalmanesh; A. Humbert; R. Ballaire; M. Diedisheim; J. B. Julla; D. Chokr; J. Cuenco; J. Michieletto; J. Charbit; D. Lindén; J. Boucher; C. Potier; A. Hamimi; S. Lemoine; C. Blugeon; P. Legoix; S. Lameiras; L. G. Baudrin; S. Baulande; A. Soprani; F. A. Castelli; F. Fenaille; J. P. Riveline; E. Dalmas; J. Rieusset; J. F. Gautier; N. Venteclef; F. Alzaid
• Keywords: 2. Zero hunger; 570; 0303 health sciences; [SDV]Life Sciences [q-bio]; Science; Macrophages; Q; 610; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Article; Monocytes; Mice; 03 medical and health sciences; Adipose Tissue; Interferon Regulatory Factors; Animals; Obesity

AbstractAdipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.