Ligand-Dependent Actions of the Vitamin D Receptor Are Required for Activation of TGF-β Signaling during the Inflammatory Response to Cutaneous Injury

The vitamin D receptor (VDR) has both 1,25-dihydroxyvitamin D-dependent and -independent actions in the epidermis. Ligand-dependent actions of the VDR have been shown to promote keratinocyte differentiation and to regulate formation of the epidermal barrier. In contrast, the actions of the VDR that regulate postmorphogenic hair cycling do not require 1,25-dihydroxyvitamin D. The VDR also has immunomodulatory actions that are dependent on its ligand, 1,25-dihydroxyvitamin D. To determine whether the ligand-dependent or -independent actions of the VDR regulate the inflammatory response to cutaneous injury, studies were performed in control, VDR knockout, and vitamin D-deficient mice. These investigations demonstrate that absence of receptor or ligand impairs the dermal response to cutaneous injury. Although neutrophil recruitment is not affected, the absence of VDR signaling leads to defects in macrophage recruitment and granulation tissue formation. Studies performed to identify the molecular basis for this phenotype demonstrate that absence of the VDR, or its ligand, impairs TGF-β signaling in the dermis, characterized by decreased expression of monocyte chemotactic protein-1 and reduced phosphorylation of phosphorylated Smad-3 as well as attenuated phosphorylated Smad-3 phosphorylation in response to TGF-β in primary dermal fibroblasts lacking the VDR. Thus, these data demonstrate that the liganded VDR interacts with the TGF-β signaling pathway to promote the normal inflammatory response to cutaneous injury.