1,25(OH)(2)D(3) Promotes Macrophage Efferocytosis Partly by Upregulating ASAP2 Transcription via the VDR-Bound Enhancer Region and ASAP2 May Affect Antiviral Immunity.
1,25(OH)(2)D(3) Promotes Macrophage Efferocytosis Partly by Upregulating ASAP2 Transcription via the VDR-Bound Enhancer Region and ASAP2 May Affect Antiviral Immunity.
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1,25(OH)2D3 部分通过 VDR 结合增强子区域上调 ASAP2 转录来促进巨噬细胞胞吞作用，并且 ASAP2 可能会影响抗病毒免疫
作者：
Shi H;Duan J;Wang J;Li H;Wu Z;Wang S;Wu X;Lu M
维生素D3的活性形式，即，1，25（OH）2D 3对免疫系统，特别是巨噬细胞介导的先天免疫，发挥抗炎作用。在先前的研究中，我们确定了THP-1细胞中1，25（OH）2D 3响应和维生素D受体（VDR）结合的超级增强子区域。本研究旨在探讨1，25（OH）2D 3通过与VDR结合的第一内含子中的超级增强子区域对具有SH 3结构域、锚蛋白重复序列和PH结构域2（ASAP 2）（编码GTP酶激活蛋白）的ArfGAP的转录调控以及ASAP 2在巨噬细胞中的潜在功能。首先，我们验证了THP-1细胞和巨噬细胞中1，25（OH）2D 3对ASAP 2的上调。随后，我们确定了三个监管区域（即，ASAP 2的VDR结合增强子中的核心、1，25（OH）2D 3-响应和抑制区域）。ASAP 2在体外促进RAC 1活性和巨噬细胞吞噬功能。接下来，我们通过质谱和RNA测序分析评估了ASAP 2的功能。ASAP 2上调抗病毒相关基因的表达，并与SAM和含HD结构域的脱氧核苷三磷酸三磷酸水解酶1（SAMHD 1）相互作用。在体内，维生素D减少了实验性自身免疫性脑脊髓炎（EAE）中的凋亡细胞数量，并促进了腹膜炎中的巨噬细胞吞噬，而不改变ASAP 2的mRNA水平。因此，我们可以更好地了解ASAP 2转录的调控机制和ASAP 2的功能，这可能是一个潜在的治疗目标，对炎症性疾病和病毒感染。
The active form of vitamin D3, i.e., 1,25(OH)2D3, exerts an anti-inflammatory effect on the immune system, especially macrophage-mediated innate immunity. In a previous study, we identified 1,25(OH)2D3-responsive and vitamin D receptor (VDR)-bound super-enhancer regions in THP-1 cells. Herein, we examined the transcriptional regulation of ArfGAP with SH3 Domain, Ankyrin Repeat and PH Domain 2 (ASAP2) (encoding a GTPase-activating protein) by 1,25(OH)2D3 through the top-ranked VDR-bound super-enhancer region in the first intron of ASAP2 and potential functions of ASAP2 in macrophages. First, we validated the upregulation of ASAP2 by 1,25(OH)2D3 in both THP-1 cells and macrophages. Subsequently, we identified three regulatory regions (i.e., the core, 1,25(OH)2D3-responsive, and inhibitory regions) in the VDR bound-enhancer of ASAP2. ASAP2 promoted RAC1-activity and macrophage efferocytosis in vitro. Next, we assessed the functions of ASAP2 by mass spectrometry and RNA sequencing analyses. ASAP2 upregulated the expressions of antiviral-associated genes and interacted with SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1). In vivo, vitamin D reduced the number of apoptotic cells in experimental autoimmune encephalomyelitis (EAE) and promoted macrophage efferocytosis in peritonitis without changing the mRNA level of ASAP2. Thus, we could better understand the regulatory mechanism underlying ASAP2 transcription and the function of ASAP2, which may serve as a potential treatment target against inflammatory diseases and virus infections.
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DOI：
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