095 Loss of loricrin exacerbates psoriasis-like skin inflammation through altered dendritic cell homeostasis

Abstract

Psoriasis is a chronic inflammatory skin disease associated with multiple predisposing factors, and one of susceptible loci known as PSORS4 is on human chromosome 1, in which epidermal differentiation complex (EDC) is located. An EDC gene loricrin (Lor) accounts for a major protein mass of cornified cell envelope (CE), the vital structure for epidermal integrity. In contrast to competent epidermal permeability barrier, Lor knockout (LKO) mice had reduced epidermal mechanical stability of the epidermis resulting from impaired cross-linking of filaggrin and keratin 1/10 in their CEs. Since mechanical stress/trauma can contribute to psoriasis induction and exacerbation, we evaluated the impact of the loss LOR in a psoriasis-like disease model. Reflecting mechanical weakness, application of mechanical stress onto the ear skin resulted in enhanced and sustained keratin 6 (K6) protein expression in LKO epidermis as determined by immunohistochemistry (IHC). LKO mice had significantly increased expression levels of cytokines that initiate psoriatic inflammatory response, including Tnf, Il1b and Ifn1a on quantitative reverse transcription PCR (RT-qPCR). Topical application of imiquimod (Aldara) cream on LKO mice resulted in a severe inflammatory phenotype; ear skin had augmented swelling, and back skin had enhanced erythema and hyperkeratosis accompanied by increased transcriptional expression levels of K6a. Since Ifn-a produced by plasmacytoid dendritic cell (pDC) is known to play a pivotal role in this model, pDC marker expression was analyzed in a steady state. Unchallenged LKO mice had significantly enhanced expression of Bst2 in the ear skin as determined by RT-qPCR and IHC. Taken together, these results indicate that reduced mechanical stability in the epidermis can exacerbate psoriasis-like skin inflammation through the alteration of DC homeostasis.