The Psoriasis Therapeutic Potential of a Novel Short Laminin Peptide C16.

Tsung-Chuan Ho,Shu-I Yeh,Show-Li Chen,Yeou-Ping Tsao

doi:10.3390/ijms20133144

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by excessive growth of keratinocytes and hyperkeratosis in the epidermis. An abnormality of the non-lesional epidermis at an early stage of psoriasis is involved in triggering inflammatory cell infiltration into the dermis. Integrin α5β1 acts as a receptor for fibronectin and has been found to be overexpressed in non-lesional psoriatic epidermis. To investigate whether α5β1 integrin has a potential as a drug target for psoriasis treatment, the α5β1 integrin-binding peptide, C16, was used to obstruct the HaCat keratinocyte cellular responses induced by fibronectin (Fn) in culture and psoriasis-like skin inflammation induced in mice by imiquimod (IMQ). The C16 exhibited antagonistic activity against α5β1 integrin in HaCat cells, with evidence of suppression of the Fn-mediated proliferative, cytoskeletal, and inflammatory responses. Topical treatment with C16 greatly reduced the IMQ-induced epidermal hyperplasia, infiltration of neutrophils/macrophages, and expression of pro-inflammatory mediators in mouse skin. The C16SP (C16-derived short peptide; DITYVRLKF) also exhibited antagonistic activity, suppressing α5β1 integrin activity in culture, and reducing IMQ-induced skin inflammation. Taken together, this study provides the first evidence that α5β1 integrin may be a potential drug target for psoriasis. The synthetic C16 peptide may serve as an agent for psoriasis therapy.

Highlights

Psoriasis is a chronic inflammatory skin disorder characterized by immune cell infiltration in the skin dermis, concomitant with hyperproliferation of epidermal keratinocytes, leading to a thickening of the epidermis and stratum corneum
Integrins are a family of transmembrane receptors consisting of an alpha and a beta chain that interact with the extracellular matrix (ECM) to mediate cell behavior, including growth, differentiation, adhesion, and motility [3]
Immunofluorescence staining of FA components, including focal adhesion kinase (FAK) and F-actin, showed that nearly 86% of cells were expressed marked FA and formed fine stress fibers (Figure 1b,c; C16 solvent as control)

Summary

Introduction

Psoriasis is a chronic inflammatory skin disorder characterized by immune cell infiltration in the skin dermis, concomitant with hyperproliferation of epidermal keratinocytes, leading to a thickening of the epidermis and stratum corneum. It has been reported that α5β1 integrin is overexpressed in the non-lesional psoriatic epidermis, compared with normal skin [4,5,6]. The overexpression of integrin α5β1 in keratinocytes of transgenic mice results in epidermal hyperproliferation, and skin inflammation, providing a possible explanation for its pathogenic role [7]. Integrin α5β1 is the primary receptor for fibronectin (Fn) [5,8]. Their interaction has been reported to induce proliferative signaling in endothelial cells and smooth muscle cells [9,10]. It is yet to be determined whether an α5β1 integrin antagonist is able to reduce the abnormal keratinocyte proliferation in psoriatic skin

Methods

Results

Conclusion