1,25-Dihydroxyvitamin D regulates macrophage activation through FBP1/PKR and ameliorates arthritis in TNF-transgenic mice

1,25-Dihydroxyvitamin D (1,25(OH)₂D₃) has immunomodulatory activity and its deficiency correlates with rheumatoid arthritis (RA) incidence. Whether 1,25(OH)₂D₃ modulates macrophage activation or protects against RA remains unclear. We demonstrate that 1,25(OH)₂D₃ suppresses M1 macrophage polarization and CD80, IL-6, CXCL10, IFIT1, IFI44, and double-stranded RNA-dependent protein kinase R (PKR) expression in the macrophages of RA patients. In phorbol 12-myristate 13-acetate-induced THP-1 cells, 1,25(OH)₂D₃ upregulates fructose-1,6-bisphosphatase 1 (FBP1) expression through direct promoter interaction. FBP1 interacts with PKR and promotes PKR ubiquitination degradation. SiR-FBP1 transfection impairs 1,25(OH)₂D₃ action and suppresses IL-6, CXCL10, IFIT1, IFI27, and IFI44 expression in macrophages, whereas siR-PKR transfection impairs siR-FBP1 activity in 1,25(OH)₂D₃-treated macrophages. 1,25(OH)₂D₃ treatment ameliorates the clinical signs of arthritis in tumor necrosis factor-transgenic mice, inhibits M1 polarization and marker expression, and promotes FBP1 expression in mononuclear cells isolated from swollen joints; thus, 1,25(OH)₂D₃ suppresses M1 macrophage activation through FBP1/PKR and ameliorates arthritis by restoring the macrophage subtype.