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Vitamin D Regulates MerTK-Dependent Phagocytosis in Human Myeloid Cells
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-15 , DOI: 10.4049/jimmunol.2000129
Jelani Clarke 1 , Moein Yaqubi 1 , Naomi C Futhey 1 , Sara Sedaghat 1 , Caroline Baufeld 2 , Manon Blain 1 , Sergio Baranzini 3 , Oleg Butovsky 2 , Jack Antel 1 , John H White 4, 5 , Luke M Healy 6
Affiliation  

Key Points Calcitriol downregulates MerTK expression in human macrophages and microglia. Calcitriol inhibits MerTK-mediated phagocytosis of myelin and apoptotic T cells. Inflammation increases CYP27B1-mediated metabolism of 25OHD and MerTK inhibition. Visual Abstract Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis. The major circulating metabolite of vitamin D (25-hydroxyvitamin D) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1. In multiple sclerosis lesions, the tyrosine kinase MerTK expressed by myeloid cells regulates phagocytosis of myelin debris and apoptotic cells that can accumulate and inhibit tissue repair and remyelination. In this study, we explored the effect of calcitriol on homeostatic (M-CSF, TGF-β–treated) and proinflammatory (GM-CSF–treated) human monocyte-derived macrophages and microglia using RNA sequencing. Transcriptomic analysis revealed significant calcitriol-mediated effects on both Ag presentation and phagocytosis pathways. Calcitriol downregulated MerTK mRNA and protein expression in both myeloid populations, resulting in reduced capacity of these cells to phagocytose myelin and apoptotic T cells. Proinflammatory myeloid cells expressed high levels of CYP27B1 compared with homeostatic myeloid cells. Only proinflammatory cells in the presence of TNF-α generated calcitriol from 25-hydroxyvitamin D, resulting in repression of MerTK expression and function. This selective production of calcitriol in proinflammatory myeloid cells has the potential to reduce the risk for autoantigen presentation while retaining the phagocytic ability of homeostatic myeloid cells.

中文翻译:

维生素 D 调节人骨髓细胞中依赖 MerTK 的吞噬作用

关键点骨化三醇下调人巨噬细胞和小胶质细胞中的 MerTK 表达。Calcitriol 抑制 MerTK 介导的髓鞘和凋亡 T 细胞的吞噬作用。炎症会增加 CYP27B1 介导的 25OHD 代谢和 MerTK 抑制。视觉摘要 维生素 D 缺乏是多发性硬化症发展的主要环境风险因素。维生素 D 的主要循环代谢物(25-羟基维生素 D)被羟化酶 CYP27B1 转化为活性形式(骨化三醇)。在多发性硬化病变中,髓细胞表达的酪氨酸激酶 MerTK 调节髓鞘碎片和凋亡细胞的吞噬作用,这些细胞可以积累并抑制组织修复和髓鞘再生。在这项研究中,我们探讨了骨化三醇对体内平衡(M-CSF、TGF-β 处理)和促炎(GM-CSF 处理)人单核细胞衍生的巨噬细胞和小胶质细胞,使用 RNA 测序。转录组学分析揭示了骨化三醇介导的对 Ag 呈递和吞噬作用途径的显着影响。骨化三醇下调两种髓细胞群中的 MerTK mRNA 和蛋白质表达,导致这些细胞吞噬髓鞘和凋亡 T 细胞的能力降低。与稳态骨髓细胞相比,促炎骨髓细胞表达高水平的 CYP27B1。只有在 TNF-α 存在下的促炎细胞才能从 25-羟基维生素 D 中产生骨化三醇,从而抑制 MerTK 的表达和功能。
更新日期:2020-06-15
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