缺血再灌注肾损伤（IRI-AKI）修复期肾脏巨噬细胞（M）持续朝M2极化，引起细胞外基质堆积是肾脏纤维化的关键机制之一。干扰素调节因子（IRF）4是调控M2极化的重要转录因子。我们的前期工作发现，敲除巨噬细胞 IRF4可减轻IRI-AKI后M2极化并减轻肾纤维化。IRF4如何调控M2极化？进一步，我们观察到M敲除IRF4可阻断芳香烃受体（AhR）转录，而AhR本身是调节免疫细胞分化的重要转录因子，生物信息学分析其启动子存在可能结合IRF4的序列。因此，我们提出IRF4可能通过增强AhR转录，从而介导M2极化促进肾脏纤维化的假说。本项目拟在巨噬细胞敲除AhR的小鼠IRI-AKI模型中研究IRF4/AhR对M2极化的作用；进一步在体外采用ChIP和基因突变技术，研究IRF4和AhR启动子的相互作用。这些工作将揭示IRI-AKI修复期M2持续极化的调控机制，为防治肾纤维化提供新的思路和治疗靶点。

Severe ischemia-reperfusion associated acute kidney injury (IRI-AKI) leads to renal fibrosis , in which sustained alternative activated macrophage(M2) polarization plays a pivotal role during the late repair phase of severe AKI by producing sustained TGF-beta and extracellular matrix components, and subsequently contributes to renal fibrosis. Interferon regulatory factor 4 (IRF4) is an important transcriptional factor that regulates M2. Our recent preliminary data showed that macrophage-specific knockout (KO) IRF4 reduced M2 polarization and thus alleviated renal fibrosis. Our findings suggest IRF4 promotes kidney fibrogenesis, but how? We further observed that IRF4 decreased the transcription of Aryl hydrocarbon receptor (AhR, another important transcriptional factor for immune cells) and its downstream target genes. Bio-informatics analysis from GENECARDS bank indicates there is IRF4-binding sequence in AhR’s promotor domain. Therefore, we raise the hypothesis that IRF4 may mediate sustained M2 polarization via AhR on renal fibrosis following ischemic reperfusion kidney injury. In this proposal, macrophage specific deletion of AhR mice are used to establish IRI-AKI model to investigate the role of AhR in M2 polarization and renal fibrosis. To further explore the relationship between IRF4 and AhR, IL4/IL13 stimulation were used to induce M2 in vitro, and we use ChIP and gene mutation to demonstrate their binding sequence. Our study will provide significant insight into the mechanism by which IRF4 promotes renal fibrosis after IRI-AKI. Manipulation of IRF4 might be a novel approach for the prevent and treatment of renal fibrosis.