1,25(OH)D Promotes Macrophage Efferocytosis Partly by Upregulating Transcription via the VDR-Bound Enhancer Region and ASAP2 May Affect Antiviral Immunity.

The active form of vitamin D, i.e., 1,25(OH)D, exerts an anti-inflammatory effect on the immune system, especially macrophage-mediated innate immunity. In a previous study, we identified 1,25(OH)D-responsive and vitamin D receptor (VDR)-bound super-enhancer regions in THP-1 cells. Herein, we examined the transcriptional regulation of () (encoding a GTPase-activating protein) by 1,25(OH)D through the top-ranked VDR-bound super-enhancer region in the first intron of and potential functions of ASAP2 in macrophages. First, we validated the upregulation of by 1,25(OH)D in both THP-1 cells and macrophages. Subsequently, we identified three regulatory regions (i.e., the core, 1,25(OH)D-responsive, and inhibitory regions) in the VDR bound-enhancer of . 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 . Thus, we could better understand the regulatory mechanism underlying transcription and the function of ASAP2, which may serve as a potential treatment target against inflammatory diseases and virus infections.