Chongqing University Central Hospital and Chongqing Emergency Medical Center, Chongqing, China; School of Public Health, Medical College of Soochow University, Suzhou, China.
School of Public Health, Medical College of Soochow University, Suzhou, China.
J Nutr Biochem. 2022 Dec;110:109148. doi: 10.1016/j.jnutbio.2022.109148. Epub 2022 Aug 29.
Silicosis is one of the severest occupational diseases worldwide, manifesting as infiltration of inflammatory cells, excessive secretion of pro-inflammatory mediators and pulmonary diffuse fibrosis. Macrophages polarization to M2 is one of the major strategies that attenuates inflammatory response. Our previous study found that vitamin D could protect against silica-induced lung injury by damping the secretion of pro-inflammatory cytokines. Here we further identified that vitamin D attenuated silica particles-induced lung inflammation by regulating macrophage polarization in a KLF4-STAT6 manner. Myeloid-specific Stat6 knockout (cKO) mice were generated for in vivo studies. Primary macrophages purified from bronchoalveolar lavage fluid (BALF) of wildtype or Stat6 cKO mice and differentiated THP-1 cells were used for in vitro studies. Vitamin D was found to promote alveolar macrophage polarizing to M2 phenotype through the STAT6 signaling pathway, as demonstrated by worse lung inflammation and ablated protection of vitamin D in silica particles-instilled Stat6 cKO mice. Mechanismly, vitamin D upregulated KLF4 expression in the alveolar macrophage, which synergistically activated STAT6. Additionally, KLF4 was found to upregulate macrophages autophagy, which protected them from silica particles-induced oxidative stress and cell apoptosis. The protective effects of vitamin D were dismissed by silencing KLF4. Our study demonstrates the potential mechanism of vitamin D-mediated macrophage polarization and reveals the therapeutic application of vitamin D in inflammatory disease.
矽肺是全球最严重的职业病之一，其特征为炎症细胞浸润、促炎介质过度分泌和弥漫性肺纤维化。巨噬细胞向 M2 极化是减轻炎症反应的主要策略之一。我们之前的研究发现，维生素 D 通过抑制促炎细胞因子的分泌，可防止二氧化硅引起的肺损伤。在这里，我们进一步确定维生素 D 通过 KLF4-STAT6 途径调节巨噬细胞极化来减轻二氧化硅颗粒诱导的肺炎症。我们生成了骨髓细胞特异性 Stat6 敲除 (cKO) 小鼠用于体内研究。从野生型或 Stat6 cKO 小鼠的支气管肺泡灌洗液 (BALF) 中纯化的原代巨噬细胞和分化的 THP-1 细胞用于体外研究。研究发现，维生素 D 通过 STAT6 信号通路促进肺泡巨噬细胞向 M2 表型极化，这表现在二氧化硅颗粒注入 Stat6 cKO 小鼠中，肺炎症加重和维生素 D 的保护作用消失。机制上，维生素 D 在肺泡巨噬细胞中上调 KLF4 的表达，从而协同激活 STAT6。此外，还发现 KLF4 可上调巨噬细胞自噬，从而保护它们免受二氧化硅颗粒诱导的氧化应激和细胞凋亡。沉默 KLF4 可消除维生素 D 的保护作用。本研究阐明了维生素 D 介导的巨噬细胞极化的潜在机制，并揭示了维生素 D 在炎症性疾病中的治疗应用。
