巨噬细胞是胆汁淤积性肝病发病机制中的关键因素。Arid3a在造血干细胞、B淋巴细胞和肿瘤细胞的生物学特性中起着重要作用，但其在胆汁淤积状态下调节巨噬细胞功能的能力尚不明确。我们采用q-PCR、免疫组化、免疫荧光染色和流式细胞术对基因和蛋白表达及细胞定位进行评估。我们制备了特异性敲除巨噬细胞Arid3a基因的小鼠，并建立了三种胆汁淤积小鼠模型。通过RNA-seq进行转录组分析。我们使用Mertk受体的特异性抑制剂在体内外进行实验。通过对Arid3a和荧光素酶报告基因的ChIP-seq对C端对核球蛋白和基因调控进行测定。在胆汁淤积小鼠模型中，巨噬细胞特异性Arid3a缺失减轻了胆汁淤积性肝损伤，并伴随巨噬细胞堆积减少。Arid3a缺失的巨噬细胞表现出更具修复性的表型，而体外添加UNC2025（一种特异性efferocytosis受体Mertk抑制剂）则消除了这种修复效应。通过上调Mertk来促进Arid3a缺失的巨噬细胞对凋亡胆管细胞的efferocytosis。Arid3a通过直接结合基因启动子，负调控了Mertk的转录。在体内，通过靶向Mertk有效地改变了Arid3a缺失巨噬细胞和胆汁淤积的保护性表型。我们还发现，在原发性胆汁性肝硬化（PBC）和原发性胆管炎（PSC）中，Arid3a在肝巨噬细胞和循环单核细胞中上调。Mertk被相应上调，并与PBC、PSC甚至健康对照样本中的Arid3a表达呈负相关。Mertk定位在毗邻胆管细胞的局部，而Arid3a定位在PBC和PSC中大量分散在免疫细胞之间，与增生的胆管细胞之间具有更大空间距离。Arid3a通过损害Mertk介导的巨噬细胞摄食凋亡的胆管细胞，促进胆汁淤积性肝损伤。因此，Arid3a-Mertk轴是胆汁淤积性肝病的一个新的有潜力的治疗靶点。巨噬细胞在胆汁淤积性肝病的发病机制中发挥着重要作用。本研究揭示了Arid3a上调巨噬细胞表现出促炎性表型，并通过损害Mertk介导的巨噬细胞对凋亡胆管细胞的摄食作用来促进胆汁淤积性肝损伤。虽然我们揭示了摄食作用是如何在小鼠造血细胞中调节的新模式，但Arid3a对慢性肝病的调节作用需要进一步阐明。版权©2023 Elsevier B.V.发表。

Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a has a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown.Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice, and established three cholestatic murine models. The transcriptome was performed by RNA-seq. Specific inhibitor for Mertk receptor was used in vitro and in vivo. Promoter activity was determined by ChIP-seq against Arid3a and a luciferase reporter assay.In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury accompanied with decreased accumulation of macrophages. Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor for efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages by upregulating Mertk. Arid3a negatively regulated Mertk transcription by direct binding to the gene promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages and cholestasis. Arid3a was upregulated in hepatic macrophages and circulating monocytes in PBC and PSC. Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC, even healthy controls. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC.Arid3a promotes cholestatic liver injury via impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a novel promising therapeutic target for cholestatic liver diseases.Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.Copyright © 2023. Published by Elsevier B.V.