Vitamin D3-Induced Promotor Dissociation of PU.1 and YY1 Results in FcεRI Reduction on Dendritic Cells in Atopic Dermatitis

Atopic dermatitis (AD) is a severe inflammatory skin disease. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) are located in the epidermis of AD patients and contribute to the inflammatory processes. Both express robustly the high-affinity receptor for IgE, Fc epsilon RI, and thereby sense allergens. A beneficial role of vitamin D-3 in AD is discussed to be important especially in patients with allergic sensitization. We hypothesized that vitamin D-3 impacts Fc epsilon RI expression and addressed this in human ex vivo skin, in vitro Langerhans cells, and IDEC models generated from primary human precursor cells. We show in this article that biologically active vitamin D-3 [1,25(OH)(2)-D-3] significantly downregulated Fc epsilon RI at the protein and mRNA levels of the receptor's alpha-chain, analyzed by flow cytometry and quantitative RT-PCR. We also describe the expression of a functional vitamin D receptor in IDEC. 1,25(OH)(2)-D-3-mediated Fc epsilon RI reduction was direct and resulted in impaired activation of IDEC upon Fc epsilon RI engagement as monitored by CD83 expression. Fc epsilon RI regulation by 1,25(OH)(2)-D-3 was independent of maturation and expression levels of microRNA-155 and PU.1 (as upstream regulatory axis of Fc epsilon RI) and transcription factors Elf-1 and YY1. However, 1,25(OH)(2)-D-3 induced dissociation of PU.1 and YY1 from the FCER1A promotor, evaluated by chromatin immunoprecipitation. We show that vitamin D3 directly reduces Fc epsilon RI expression on dendritic cells by inhibiting transcription factor binding to its promotor and subsequently impairs IgE-mediated signaling. Thus, vitamin D-3 as an individualized therapeutic supplement for those AD patients with allergic sensitization interferes with IgE-mediated inflammatory processes in AD patients.

Automated summary

Atopic dermatitis is a severe inflammatory skin disease where Langerhans cells and IDCs express high-affinity IgE receptors and sense allergens. Vitamin D-3 can directly reduce Fc epsilon RI expression on dendritic cells, inhibiting IgE-mediated inflammatory processes in AD patients with allergic sensitization.