Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
PLoS One. 2024 Jul 23;19(7):e0306426. doi: 10.1371/journal.pone.0306426. eCollection 2024.
The vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), its nuclear receptor VDR (vitamin D receptor) and hundreds of their target genes are not only key regulators of calcium homeostasis, but also important modulators of the immune system. Innate immune cells like monocytes use VDR for efficient differentiation and are very responsive to vitamin D. So far, most information on the gene regulatory function of vitamin D and its physiological impact had been obtained from in vitro studies using supraphysiological doses of 1,25(OH)2D3. Therefore, medical experiments like the study VitDHiD (NCT03537027), where 25 healthy individuals were supplemented once with a vitamin D3 bolus (80,000 IU), provide important insight into the response to vitamin D under in vivo conditions. In this study, we inspected 452 in vivo vitamin D target genes from peripheral blood mononuclear cells (PBMCs) detected in VitDHiD and found 61 of them involved in eight major KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways of innate immunity. Under in vivo conditions in healthy individuals vitamin D either silences five pathways of innate immunity, stabilizes two and increases one, so that acute inflammation is suppressed and the release of cytokines is kept under control. A ranking of the 61 target genes by inducibility, basal expression and multiple involvements in the pathways highlighted the genes NFKBIA (NFκB inhibitor alpha), NFKBIZ, FOSL2 (FOS like 2, AP1 transcription factor subunit), JDP2 (Jun dimerization protein 2), PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1), CLEC7A (C-type lectin domain containing 7A), DUSP6 (dual specificity phosphatase 6), NCF2 (neutrophil cytosolic factor 2), PLCB1 (phospholipase C beta 1), PLCG2 and TNFAIP3 (TNF alpha induced protein 3). In conclusion, vitamin D's in vivo effect on innate immunity in healthy adults is mediated by the interconnection of the pathways of neutrophil extracellular trap formation, Toll-like receptor, chemokine and phagosome signaling, NOD-like receptor, C-type lectin receptor, apoptosis and interleukin 17 through a limited set of proteins encoded by key target genes.
维生素 D3 代谢产物 1,25-二羟维生素 D3（1,25(OH)2D3）、其核受体 VDR（维生素 D 受体）及其数百个靶基因不仅是钙稳态的关键调节剂，也是免疫系统的重要调节剂。先天免疫细胞，如单核细胞，使用 VDR 进行有效的分化，并且对维生素 D 非常敏感。到目前为止，关于维生素 D 的基因调控功能及其生理影响的大多数信息都是通过使用超生理剂量的 1,25(OH)2D3 进行体外研究获得的。因此，像 VitDHiD（NCT03537027）这样的医学实验，其中 25 名健康个体一次性补充维生素 D3 弹丸（80,000IU），提供了对体内条件下维生素 D 反应的重要见解。在这项研究中，我们检查了 VitDHiD 中从外周血单核细胞（PBMCs）中检测到的 452 个体内维生素 D 靶基因，发现其中 61 个参与先天免疫的八个主要 KEGG（京都基因与基因组百科全书）途径。在健康个体的体内条件下，维生素 D 要么沉默先天免疫的五个途径，要么稳定两个途径并增加一个途径，从而抑制急性炎症并控制细胞因子的释放。通过可诱导性、基础表达和途径中的多重参与对 61 个靶基因进行排序，突出了基因 NFKBIA（NFκB 抑制剂 alpha）、NFKBIZ、FOSL2（FOS 样 2，AP1 转录因子亚基）、JDP2（Jun 二聚化蛋白 2）、PIK3R1（磷脂酰肌醇-3-激酶调节亚基 1）、CLEC7A（C 型凝集素域包含 7A）、DUSP6（双重特异性磷酸酶 6）、NCF2（中性粒细胞胞质因子 2）、PLCB1（磷脂酶 C beta 1）、PLCG2 和 TNFAIP3（TNF alpha 诱导蛋白 3）。总之，维生素 D 对健康成年人先天免疫的体内作用是通过连接形成中性粒细胞胞外陷阱、Toll 样受体、趋化因子和吞噬体信号、NOD 样受体、C 型凝集素受体、细胞凋亡和白细胞介素 17 的途径来介导的，通过一组有限的由关键靶基因编码的蛋白质。
