RT Journal Article SR Electronic T1 IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+ macrophage phenotype JF bioRxiv FD Cold Spring Harbor Laboratory SP 601963 DO 10.1101/601963 A1 Alastair L. Corbin A1 Maria Gomez-Vazquez A1 Tariq E. Khoyratty A1 Dorothée L. Berthold A1 Hannah Almuttaqi A1 Moustafa Attar A1 Isabelle C. Arnold A1 Fiona M. Powrie A1 Stephen N. Sansom A1 Irina A. Udalova YR 2019 UL http://biorxiv.org/content/early/2019/04/07/601963.abstract AB Mononuclear phagocytes (MNPs) play a key role in maintaining intestinal homeostasis but also in triggering immunopathology in response to acute microbial stimulation, which induces the recruitment of masses of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon Regulatory Factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state, but ameliorates immunopathology during Helicobacter hepaticus induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single cell RNA-sequencing approaches we compare the differentiation trajectories of wild type and IRF5 deficient monocytes in a shared inflammatory environment and demonstrate that IRF5 stipulates a choice in monocyte differentiation towards macrophages. Specifically, IRF5 promotes the generation of pathogenic CD11c+ macrophages and controls the production of inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional controller of pathogenic monocyte differentiation in the gut.