Abstract
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)(2)D(3), has an immunomodulatory effect on reprogramming macrophages towards an M2 phenotype. This review examines the molecular mechanisms through which 1,25(OH)(2)D(3) is reported to influence macrophage metabolism, surface marker expression, and intracellular signalling. Overall, the review suggests that 1,25(OH)(2)D(3)-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)(2)D(3) action in COPD macrophages and validating its clinical effects as part of personalised treatment strategies. Evidence suggests that 1,25(OH)(2)D(3) enhances mitochondrial function and shift macrophage metabolism from glycolysis to oxidative phosphorylation through metabolic reprogramming facilitating M1-to-M2 polarisation. 1,25(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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.