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IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation.
Science Immunology ( IF 17.6 ) Pub Date : 2020-05-22 , DOI: 10.1126/sciimmunol.aax6085
Alastair L Corbin 1 , Maria Gomez-Vazquez 1 , Dorothée L Berthold 1 , Moustafa Attar 1 , Isabelle C Arnold 1, 2 , Fiona M Powrie 1 , Stephen N Sansom 1 , Irina A Udalova 1
Affiliation  

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.

中文翻译:

IRF5引导单核细胞趋向于炎症性CD11c +巨噬细胞表型,并促进肠道炎症。

单核吞噬细胞(MNP)对于维持肠道稳态至关重要,但是,响应急性微生物刺激,也可以触发免疫病理学,加速Ly6Chi单核细胞向肠道的募集。控制肠道中单核细胞组织适应性的调节器仍然知之甚少。干扰素调节因子5(IRF5)是一种转录因子,先前显示在维持巨噬细胞的炎症表型中起关键作用。在这里,我们调查IRF5对稳态和炎症过程中MNP系统和肠道生理的影响。我们证明,IRF5缺乏对稳定状态下结肠生理的影响有限,但可以改善肝炎幽门螺杆菌引起的结肠炎的免疫病理学。MNP表型中IRF5活性的抑制表明全球IRF5缺乏。使用骨髓嵌合体和单细胞RNA测序方法的组合,我们检查了IRF5在控制结肠MNP发育中的内在作用。我们证明IRF5促进Ly6Chi单核细胞分化成CD11c +巨噬细胞,并控制这些细胞产生抗微生物和炎症介质。因此,我们确定IRF5是肠道炎症过程中结肠MNP系统的关键转录调节因子。
更新日期:2020-05-22
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