Vitamin D3-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D3 synthesis and correlates with increased CD4+ T cell CTLA-4 expression

Abstract

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)₂D₃ synthesis on vitamin D₃-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)₂D₃ synthesis was essential for vitamin D₃-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4⁺ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D₃ reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)₂D₃ production and CTLA-4 upregulation in CNS-infiltrating CD4⁺ T cells. We suggest that CTLA-4 serves as a vitamin D₃-regulated immunological checkpoint in multiple sclerosis prevention.

Keywords: Autoimmunity; Cyp27b1; EAE/MS; Gene targeting; Myeloid cells; Vitamin D.