Role of Proteases and Protease-Activated Receptor-2 in Inflammatory Skin Diseases

Abstract

Proteases and protease inhibitors are tightly regulated in skin and play an important role in epidermal permeability barrier homeostasis, inflammation, and immune responses. Proteases are involved in filaggrin processing, desquamation, degradation of lipid processing enzyme, and the regulation of the antimicrobial activity or inflammatory effect of antimicrobial peptides through proteolytic degradation. Certain serine proteases activate protease-activated receptors-2 (PAR-2) on keratinocytes and regulate inflammation, pruritus, and skin barrier homeostasis. The imbalance between proteases and their inhibitors and PAR-2 signaling have been demonstrated to contribute to the pathogenesis of several inflammatory skin disorders including atopic dermatitis, Netherton syndrome, psoriasis, rosacea, and acne. In atopic dermatitis, genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens increase epidermal protease activity, resulting in sustained barrier dysfunction, inflammation and itching sensation. In psoriasis, all kallikrein (KLK) s, cathepsin S, cathepsin D, and human airway trypsin-like protease are increased in lesional skin, suggesting a role of proteases in the pathomechanism. In rosacea, increased toll-like receptor 2 and KLK5 in keratinocytes enhance the levels of the vasoactive and inflammatory cathelicidin and its proteolytic peptide fragments, causing inflammation and vascular effects. In acne, protease released by P. acnes has been found to activate PAR-2, resulting in inflammatory responses. Taken together, these findings suggest that protease activity and PAR-2 signaling might have a role in the pathogenesis of atopic dermatitis, Netherton syndrome, psoriasis, rosacea, and acne.