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IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE129258 | GEO | 2020/04/01

REPOSITORIES: GEO

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IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [small_bulk_rnaseq]

Project description: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.

2020-04-01 | GSE129257 | GEO

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [single_cell_rnaseq]

2020-04-01 | GSE129256 | GEO

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [scrnaseq_steady_state]

2020-06-11 | GSE152198 | GEO

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype

Project description:IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype

| PRJNA530678 | ENA

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [scrnaseq_steady_state]

Project description:IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [scrnaseq_steady_state]

| PRJNA638619 | ENA

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [small_bulk_rnaseq]

Project description:IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [small_bulk_rnaseq]

| PRJNA530686 | ENA

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [single_cell_rnaseq]

Project description:IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards pathogenic CD11c+ macrophage phenotype [single_cell_rnaseq]

| PRJNA530685 | ENA

IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation.

Project description:Mononuclear phagocytes (MNPs) are vital for maintaining intestinal homeostasis but, in response to acute microbial stimulation, can also trigger immunopathology, accelerating recruitment 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 examined the intrinsic role of IRF5 in controlling colonic MNP development. We demonstrate that IRF5 promotes differentiation of Ly6Chi monocytes into CD11c+ macrophages and controls the production of antimicrobial and inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional regulator of the colonic MNP system during intestinal inflammation.

| S-EPMC7611075 | biostudies-literature

CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23.

Project description:In inflammatory bowel diseases, a breakdown in host microbial interactions accompanies sustained activation of immune cells in the gut. Functional studies suggest a key role for interleukin-23 (IL-23) in orchestrating intestinal inflammation. IL-23 can be produced by various mononuclear phagocytes (MNPs) following acute microbial stimulation, but little is known about the key cellular sources of IL-23 that drive chronic intestinal inflammation. Here we have addressed this question using a physiological model of bacteria-driven colitis. By combining conditional gene ablation and gene expression profiling, we found that IL-23 production by CD11c(+) MNPs was essential to trigger intestinal immunopathology and identified MHCII(+) monocytes and macrophages as the major source of IL-23. Expression of IL-23 by monocytes was acquired during their differentiation in the intestine and correlated with the expression of major histocompatibility complex class II (MHCII) and CD64. In contrast, Batf3-dependent CD103(+) CD11b(-) dendritic cells were dispensable for bacteria-induced colitis in this model. These studies reinforce the pathogenic role of monocytes in dysregulated responses to intestinal bacteria and identify production of IL-23 as a key component of this response. Further understanding of the functional sources of IL-23 in diverse forms of intestinal inflammation may lead to novel therapeutic strategies aimed at interrupting IL-23-driven immune pathology.

| S-EPMC4650208 | biostudies-literature

Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation

Project description:Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions. The transcription factor, IRF5, has been implicated in the regulation of inflammation, but how IRF5 protein is activated is still unclear. Here the authors use inhibitor library screening, biochemical analyses and in vivo/ex vivo data to show that a protein tyrosine kinase, Pyk2, may be key for the activation of IRF5 in macrophages and inflammatory responses in the gut.

| S-EPMC8602323 | biostudies-literature

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