833 Reintroduction of caveolin-1 scaffolding domain improves pathogenesis of psoriasiform dermatitis

Abstract

Psoriasis is a chronic, inflammatory skin disease characterized by well-defined, erythematous plaques with silvery scale secondary to aberrant keratinocyte proliferation. We have previously identified that a structural membrane protein caveolin-1 (Cav1) is involved in regulation of aberrant keratinocyte proliferation and differentiation, and thus the aim of this study was to elucidate the role of Cav1 in pathogenesis of psoriasis vulgaris. We utilized spatial genomic & proteomic analyses combined with immunohistochemistry (IHC) with patient samples and mouse models. Omics analyses identified caveolae and their structural components (Cav1, -2 and cavin-1) as downregulated in imiquimod (IMQ)-treated mouse model of psoriasis. These observations were validated in patient samples of multiple types of psoriasis stratified by PASI score (plaque, inverse, guttate and nail) by IHC staining and quantified by QuPath image analysis software. Although all biopsy samples exhibited an inverse relationship with levels of Cav1, plaque psoriasis samples were the most pronounced. To assess whether reintroduction of Cav1 can alleviate some of the features associated with IMQ-induced model of psoriasis (increased skin thickness/scaling and upregulation of psoriasis associated markers), C57BL6 and K14cre-Cav1 knockout mice were treated with soluble caveolin scaffolding domain (CSD) peptide, in presence or absence of IMQ. We observed that Cav1ko mice exhibited a trend in increased skin thickness and expression of CD11b, CD14, IL-6, IL-12, IL-17a and TNFa, although to a lesser than IMQ-treated C57BL6 mice (Cav1 wild type). Moreover, topical CSD treatment decreased both skin thickness and scaling, as well as dampened upregulation of aforementioned inflammatory markers. Together, these data support the hypothesis that Cav1 is major pathophysiological target in psoriasis and introduce different approach to localized topical treatment of psoriasis by targeting structural components of the specialized membrane microdomains, such as caveolae.