Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis

Abstract

Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/ PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD.

Fig. 1

Role of serine proteases in the epidermal permeability barrier homeostasis. aSMase, acid sphingomyelinase; β-GlcCer'ase, β-glucocerebrosidase; CDSN, corneodesmosin; DSC, desmocollin; DSG, desmoglein; KLK, kallikrein; LB, lamellar body; PAR-2, protease-activated receptor-2; SC, stratum corneum.

Fig. 2

Role of PAR-2 in the epidermal permeability barrier homeostasis. LB, lamellar body; PAR-2, protease-activated receptor-2.

Fig. 3

PAR-2 and Netherton syndrome. Ela-2, pancreatic elastase-2; KLK, kallikrein; LETKI, lympho-epithelial Kazal-type-related inhibitor; PAR-2, protease-activated receptor-2; SPINK-5, serine protease inhibitor kazal-type 5; TSLP, thymic stromal lymphopoietin.

Fig. 4

Proteases and PAR-2 in the pathogenesis of atopic dermatitis. LETKI, lympho-epithelial Kazal-type-related inhibitor; PAR-2, protease-activated receptor-2; SCCE, stratum corneum chymotrypsin-like enzyme; SCTE, stratum corneum trypsin-like enzyme; SNP, single nucleotide polymorphism.