|Public on Jun 11, 2020
|IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [scrnaseq_steady_state]
|Expression profiling by high throughput sequencing
|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.
|Mixed bone marrow chimeras (mice) were constructed using wildtype (CD45.1+ve) and Irf5 knockout (CD45.2+ve) cells that were also heterozygous for knock-in of GFP to the CX3CR1 locus. The steady state blood and cLP scRNA-seq datasets were generated in the same experiment from a set of MBMCs (n=5, cells pooled from all animals for both analyses).
|Corbin AL, Gomez-Vazquez M, Attar M, Udalova IA, Sansom SN
|Jun 10, 2020
|Last update date
|Sep 10, 2020
|Kennedy Institute of Rheumatology
|Illumina NovaSeq 6000 (Mus musculus)
|This SubSeries is part of SuperSeries:
|IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype