Protease/PAR-2 Signaling in Atopic Dermatitis airway trypsin-like protease (HAT), cathepsin G, and factor Xa have been demonstrated to activate PAR-2. In addition, some kinds of pathogenic organisms with proteolytic acti- vity such as house dust mites, cockroaches, pollens, molds or bacteria may also be exogenous activators of PAR-2. Upon activation, PAR-2, which is mainly localized to lipid raft domains under basal status, is known to be endocytosed and degraded.7,43 As a G-protein coupled receptor, PAR-2 is known to have a common signaling pathway, including the activation of phospholipase C, which results in the forma- tion of ionsitol triphosphate and diacylglycerol, followed by calcium mobilization.39 In vitro, PAR-2 activation by PAR-2 agonist peptide has been demonstrated to provoke transient intracellular calcium mobilization in primary kera- tinocytes, suggesting that PAR-2 could regulate the proli- feration and differentiation of keratinocytes.44,45 The precise role of PAR-2 in epidermal barrier homeostasis is discuss- ed below. PROTEASE/PAR-2 AND EPIDERMAL BARRIER KLKs and their inhibitors are co-localized in the LBs and secreted to the SG-SC junction. The enzyme activity of various proteases in the skin and the inhibitory activity of protease inhibitors are regulated by the SC pH gradient. These findings imply that proteases play an important role in epidermal permeability barrier homeostasis, and recent studies have further shown the importance of proteases and PAR-2 signaling in the barrier function of the skin. Pro- teases exert various cellular responses, some of which may be, in part, mediated via activation of PAR-2. Non-PAR-2-mediated function Filaggrin processing Filaggrin aggregates keratin intermediate filaments to form the cornified cell envelope, thereby providing the structural support and mechanically resilient skin barrier. In addition, these polypeptides are degraded into natural moisturizing factors (NMF), and contribute to water retention within the SC layers, helping to maintain skin hydration.46,47 A num- ber of proteases, including PEP-1, µ-calpain, furin, prosta- tin, matriptase, and caspase-14, elastase2 (ELA2), have been demonstrated to be involved in the proteolytic pro- cessing of filaggrin and profilaggrin, which leads to epi- dermal differentiation, barrier formation and hydration.32,48-52 Recently, the two membrane-bound serine proteases matri- ptase and prostasin have been reported to be involved in the processing of profilaggrin by activating the epithelial sodium channel (ENaC) which causes a calcium influx through a voltage-gated calcium channel, thereby inducing the activation of calcium-dependent proteases.31 Matriptase, or MT-SP1 is a type II trans-membrane serine protease and is now considered to be an essential component of the pro- filaggrin-processing pathway, in accordance with the observation that neonate Matriptase/MT-SP1-deficient skin displayed a loss of mature filaggrin monomer.32 Matri- ptase is also known to be co-localized with another mem- 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. Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010 811