Role of Type 3 deiodinase in normal skin and in wound healing processes

The skin is a well-known target of thyroid hormone (TH). TH action is finely controlled by the deiodinase family of enzymes, responsible of the tissue-specific activation and inactivation of the prohormone thyroxine (T4). We report that the type 3 deiodinase (D3), the principal terminator of TH action, is required for the normal epidermal proliferation. D3-depleted keratinocytes show a proliferative defect, associated with a trend toward early differentiation. K14CRE-Dio3Fl/Fl mice, in the absence of D3 only in epidermis, present an alterated epidermal phenotype characterized by a thinner epidermis, reduced levels of K14 (specific marker for the basal proliferating cells) and slowed T4 clearance. These manifestations affect on epidermal regeneration processes in which a proper balance between cellular proliferation and differentiation is strictly required. We found a massive induction of D3 during early phases of wound healing, when the cellular environment requires an increased proliferation necessary to repair the damage. Moreover, K14CRE-Dio3Fl/Fl mice show a defective wound repair compared to WT mice, with a delayed wound closure, caused by a decrease of proliferation. In conclusion, we show that the D3 enzyme is employed to attenuate TH-signaling in skin, providing a striking example of how a circulating hormone can be tissue-specifically attenuated to influence local requirement.