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

Wei Zhu, Ye Zhu, Shujun Zhang, Weiting Zhang, Zihou Si, Yuxi Bai, Ying Wu, Yao Fu, Yang Zhang, Luyao Zhang, Xiaomin Zhang, Xiaodong Zhu

The Journal of steroid biochemistry and molecular biology 2023 Apr

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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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Wei Zhu, Ye Zhu, Shujun Zhang, Weiting Zhang, Zihou Si, Yuxi Bai, Ying Wu, Yao Fu, Yang Zhang, Luyao Zhang, Xiaomin Zhang, Xiaodong Zhu. 1,25-Dihydroxyvitamin D regulates macrophage activation through FBP1/PKR and ameliorates arthritis in TNF-transgenic mice. The Journal of steroid biochemistry and molecular biology. 2023 Apr;228:106251