1,25‑Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by suppressing miR-125b.

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.