1,25‑Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by...

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)₂D₃) has immunomodulatory activity, and 1,25(OH)₂D₃ deficiency is correlated with autoimmune diseases, especially IBD. This study aimed to explore whether 1,25(OH)₂D₃ modulates macrophage polarization in inflammation. Peripheral blood mononuclear cells and colitis mice were treated with 1,25(OH)₂D₃. Macrophages were transfected with siRNA-vitamin D receptor (VDR) or miR-125b mimic or inhibitor, and 1,25(OH)₂D₃-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)₂D₃ 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)₂D₃ activity. In colitis mice, 1,25(OH)₂D₃ 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)₂D₃ action. Collectively, the results demonstrate that 1,25(OH)₂D₃ downregulates miR-125b expression and promotes M1 macrophage polarization to the M2 subtype. 1,25(OH)₂D₃ pretreatment ameliorated colitis by restoring the LPMC macrophage subtype balance.