• A Possible Role for AP-1 Transcription Factors in Development of Epidermal Ichthyoses

      Young, Christina; Eckert, Richard (Richard L.) (2017)
      Ichthyoses are highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis and hyperplasia. Some ichthyosis-related skin disorders are caused by genetic mutation while other forms are acquired. AP-1 transcription factors are known regulators proliferation and differentiation in the epidermis and their activity is necessary in achieving homeostasis of the epidermal barrier. We have previously described a mouse model where inactivation of AP-1 transcription factor function in the suprabasal epidermis, via targeted expression of a dominant negative c-jun (TAM67), produces an ichthyosis-related phenotype. The observed phenotype includes keratinocyte hyperproliferation, delayed differentiation, hyperkeratosis, parakeratosis, extensive vasodilation/erythroderma, tail and digit pseudoainhum, reduced barrier integrity, reduced filaggrin level, and nuclear accumulation of loricrin. To further characterize this mouse model, we sought out to follow phenotype development during embryogenesis. TAM67 expression was turned on during embryogenesis at embryonic day (E) E13.5, E15.5, and E17.5. The E13.5 and E15.5 treated embryos had severely decreased filaggrin levels, nuclear loricrin, and were born with a collodion baby-like phenotype as seen in many human ichthyosis patients. These data suggest a role for AP-1 transcription factors in epidermal development. Next, we focused on the downstream signaling effects of suprabasal AP-1 transcription factor inhibition in the adult mouse by assessing the role of specific chemokine mediators in phenotype development. We monitored impact on chemokine production and used knockout methods to study the role of the most highly induced chemokines in this process. Suprabasal AP-1 factor inactivation results in increased levels of Th1 (IFN?, CCL3, CCL5, CXCL9, CXCL10, and CXCL11) and Th2 (CCL1, CCL2, CCL5, and CCL11) chemokines in epidermis and serum. S100A8 and S100A9 levels are also elevated. Interestingly, we observe no attenuation of phenotype when TAM67 is expressed in the epidermis of CXCR3 (CXCL9, CXCL10, and CXCL11 receptor) or S100A8/A9 knockout mice indicating lack of a role of these regulators in phenotype development. We propose that loss of AP-1 transcription factor function leads to impaired barrier function and enhanced epidermal chemokine production. These findings suggest that reduced AP-1 transcription factor activity may play a role in the pathogenesis of ichthyosis related skin disorders.