Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China; Key Laboratory of Tumor Prevention and Treatment of Heilongjiang Province, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China.
Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China.
Int Immunopharmacol. 2019 Feb;67:106-118. doi: 10.1016/j.intimp.2018.12.015. Epub 2018 Dec 9.
Macrophages are highly plastic cells. Depending on stimulation, macrophages rapidly polarize to functionally distinct phenotypes that are involved in the pathogenesis of inflammatory bowel disease (IBD). 1,25‑Dihydroxyvitamin D (1,25(OH)D) has immunomodulatory activity, and 1,25(OH)D deficiency is correlated with autoimmune diseases, especially IBD. This study aimed to explore whether 1,25(OH)D modulates macrophage polarization in inflammation. Peripheral blood mononuclear cells and colitis mice were treated with 1,25(OH)D. Macrophages were transfected with siRNA-vitamin D receptor (VDR) or miR-125b mimic or inhibitor, and 1,25(OH)D-pretreated colitis mice were injected with a miR-125b agomir. The distribution of macrophage subsets and macrophage subtype characteristics was analyzed. As expected, 1,25(OH)D transformed lipopolysaccharide-induced M1 macrophages to the M2 subset, downregulated tumor necrosis factor-α and interleukin (IL)-6 expression and interferon regulatory factor 5 (IRF5) phosphorylation, and upregulated IL-10, arginase-1, VDR, and IRF4 expression. SiRNA-VDR and miR-125b mimic significantly impaired 1,25(OH)D activity. In colitis mice, 1,25(OH)D pretreatment ameliorated disease activity, converted M1 macrophages to the M2 subtype, suppressed IRF5 phosphorylation, and increased IRF4 expression in lamina propria mononuclear cells (LPMC). miR-125b agomir injections reversed 1,25(OH)D action. Collectively, the results demonstrate that 1,25(OH)D downregulates miR-125b expression and promotes M1 macrophage polarization to the M2 subtype. 1,25(OH)D pretreatment ameliorated colitis by restoring the LPMC macrophage subtype balance.
巨噬细胞是高度可塑性的细胞。根据刺激的不同，巨噬细胞会迅速极化，形成具有不同功能的表型，参与炎症性肠病（IBD）的发病机制。1,25-二羟维生素 D（1,25（OH）2D）具有免疫调节活性，1,25（OH）2D 缺乏与自身免疫性疾病有关，尤其是 IBD。本研究旨在探讨 1,25（OH）2D 是否调节炎症中的巨噬细胞极化。用 1,25（OH）2D 处理外周血单核细胞和结肠炎小鼠。用 siRNA-维生素 D 受体（VDR）或 miR-125b 模拟物或抑制剂转染巨噬细胞，并用 miR-125b 激动剂预处理结肠炎小鼠。分析了巨噬细胞亚群的分布和巨噬细胞亚型特征。正如预期的那样，1,25（OH）2D 将脂多糖诱导的 M1 巨噬细胞转化为 M2 亚群，下调肿瘤坏死因子-α和白细胞介素（IL）-6 的表达和干扰素调节因子 5（IRF5）磷酸化，上调 IL-10、精氨酸酶-1、VDR 和 IRF4 的表达。siRNA-VDR 和 miR-125b 模拟物显著削弱了 1,25（OH）2D 的活性。在结肠炎小鼠中，1,25（OH）2D 预处理可改善疾病活动，将 M1 巨噬细胞转化为 M2 亚型，抑制固有层单核细胞（LPMC）中 IRF5 磷酸化，增加 IRF4 表达。miR-125b 激动剂的注射逆转了 1,25（OH）2D 的作用。综上所述，结果表明 1,25（OH）2D 下调 miR-125b 的表达并促进 M1 巨噬细胞向 M2 亚型极化。1,25（OH）2D 预处理通过恢复 LPMC 巨噬细胞亚型平衡来改善结肠炎。
