Thai Hy, Hassanen Rei, Whittall Trevor, Kirkham Paul
School of Applied Sciences, University of the West of England, Bristol, UK.
Department of Biomedical Sciences and Physiology, University of Wolverhampton, Wolverhampton, UK.
J Inflamm (Lond). 2025 Jul 1;22(1):26. doi: 10.1186/s12950-025-00452-y.
Macrophages play an important role in tissue homeostasis, inflammation, and repair, displaying remarkable plasticity by polarising towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes. In chronic obstructive pulmonary disease (COPD), this regulatory balance is disrupted, resulting in sustained tissue damage and impaired repair capability. Defective efferocytosis and dysregulated macrophage phenotypes are key contributors to COPD pathogenesis. Emerging evidence suggests that vitamin D3, particularly its active form 1,25(OH)D, has an immunomodulatory effect on reprogramming macrophages towards an M2 phenotype. This review examines the molecular mechanisms through which 1,25(OH)D is reported to influence macrophage metabolism, surface marker expression, and intracellular signalling. Overall, the review suggests that 1,25(OH)D-mediated reprogramming of macrophage phenotype and function offers a potential therapeutic approach to mitigate persistent inflammation and tissue destruction in COPD. Moreover, future research should focus on exploring the detailed molecular pathway of 1,25(OH)D action in COPD macrophages and validating its clinical effects as part of personalised treatment strategies. Evidence suggests that 1,25(OH)D enhances mitochondrial function and shift macrophage metabolism from glycolysis to oxidative phosphorylation through metabolic reprogramming facilitating M1-to-M2 polarisation. 1,25(OH)D also modulates macrophage phenotype by regulating M2-associated surface markers (CD36, CD163, CD206, TIM-3) and downregulating pro-inflammatory mediators (CD86, iNOS, HLA-DR). It promotes the secretion of anti-inflammatory cytokines IL-10 and TGF-β while suppressing IL-1β, IL-6 and TNF production. Mechanistically, 1,25(OH)D regulates macrophage polarisation through multiple signalling pathways and suppresses pro-inflammatory responses by inhibiting NF-κB and MAPK activation, while promoting anti-inflammatory signalling via STAT6 and VDR-PPARγ axis. Deficiency in 1,25(OH)D is strongly associated with increased inflammation and oxidative stress in COPD correlating with increased disease severity. Conversely, restoring vitamin D3 levels reduces oxidative damage, suppresses pro-inflammatory gene expression, and improves alveolar macrophage function highlighting its therapeutic potential in modulating inflammation.
巨噬细胞在组织稳态、炎症和修复中发挥重要作用，通过向促炎性M1或抗炎性M2表型极化表现出显著的可塑性。在慢性阻塞性肺疾病（COPD）中，这种调节平衡被打破，导致持续的组织损伤和修复能力受损。吞噬功能缺陷和巨噬细胞表型失调是COPD发病机制的关键因素。新出现的证据表明，维生素D3，特别是其活性形式1,25(OH)D，对将巨噬细胞重编程为M2表型具有免疫调节作用。本综述探讨了据报道1,25(OH)D影响巨噬细胞代谢、表面标志物表达和细胞内信号传导的分子机制。总体而言，该综述表明1,25(OH)D介导的巨噬细胞表型和功能重编程为减轻COPD中的持续炎症和组织破坏提供了一种潜在的治疗方法。此外，未来的研究应集中于探索1,25(OH)D在COPD巨噬细胞中的详细作用分子途径，并验证其作为个性化治疗策略一部分的临床效果。有证据表明，1,25(OH)D通过代谢重编程促进M1向M2极化，增强线粒体功能并将巨噬细胞代谢从糖酵解转变为氧化磷酸化。1,25(OH)D还通过调节与M2相关的表面标志物（CD36、CD163、CD206、TIM-3）和下调促炎介质（CD86、iNOS、HLA-DR）来调节巨噬细胞表型。它促进抗炎细胞因子IL-10和TGF-β的分泌，同时抑制IL-1β、IL-6和TNF的产生。从机制上讲，1,25(OH)D通过多种信号通路调节巨噬细胞极化，并通过抑制NF-κB和MAPK激活来抑制促炎反应，同时通过STAT6和VDR-PPARγ轴促进抗炎信号传导。1,25(OH)D缺乏与COPD中炎症和氧化应激增加密切相关，这与疾病严重程度增加相关。相反，恢复维生素D3水平可减少氧化损伤，抑制促炎基因表达，并改善肺泡巨噬细胞功能，突出了其在调节炎症方面的治疗潜力。
