723 Common and different roles of dermokine in skin diseases based on mouse genetic background

Dermokine (DMKN) is a secreted glycoprotein expressed predominantly in the upper epidermis, particularly granular layers, whose expression pattern resembles the terminal differentiation molecules. It comprises three splice variants in mice and five in humans. Our recent investigation generating all three isoforms of DMKN deficiency in C57BL/6 mice [DMKN-KO(B6)] demonstrated ichthyosiform skin with transepidermal water imbalance, Th17-prone immune response, and average molecular permeability in the early neonatal stage, resulting in lethal under low humidity. In adult DMKN-KO(B6), the imiquimod- and IL-23-induced psoriasis models were exacerbated, while the atopic model induced by ovalbumin transdermal sensitization was comparable to the wild-type. However, the influence of DMKN deficiency may also depend on the genetic background of the mice. Therefore, we newly established DMKN-KO mice on a BALB/c background [DMKN-KO(BALB/c)]. The DMKN-KO(BALB/c) reproduced ichthyosiform skin in the neonatal period but was somewhat milder and with a better prognosis than DMKN-KO(B6). Unlike the experimental findings on the B6 background, the transcutaneous sensitization and elicitation with ovalbumin exhibited a significantly higher serum titer of antigen-specific IgE in DMKN-KO(BALB/c) than in DMKN-KO(B6) and wild-type(BALB/c). Consistent with this, skin thickness and inflammatory cell infiltration were also exacerbated in DMKN(BALB/c). The phenotype and inflammatory cell infiltration of imiquimod- and recombinant IL-23-induced psoriasis models were as aggravated in DMKN-KO(BALB/c) as in DMKN-KO(B6). The expression of disease-related cytokines in lesional skin correlated with the severity of each model. Exacerbation by the recombinant IL-23 subcutaneous injection suggests that secreted DMKN acts on skin immunity independently of its role in maintaining homeostasis of the keratinization and barrier function. DMKN may have unique regulatory roles in the pathogenesis of ichthyosis, atopic dermatitis, and psoriasis, depending on the immunogenetic background.