Protease/PAR-2 Signaling in Atopic Dermatitis base application in murine skin leads to degradation of both β-glucocerebrosidase (β-GlcCer’ase) and acid sphingomye- linase (aSMase) and consequent defect of epidermal barrier function, which was reversed by coapplied SP inhibitors. In addition to this direct proteolytic effect, serine proteases could affect LB secretion via PAR-2 activation.7 Control of antimicrobial function in skin Antimicrobial peptides (AMPs) are important molecules that comprise the innate immune defense system of the skin. Besides their antimicrobial activity, AMPs in skin have been known to have multiple functions, including modulation of host imflammatory responses and promo- tion of wound healing.59 Moreover, previous study has sug- gested that AMPs are associated with permeability barrier function by showing a significant delay in permeability barrier recovery after tape stripping and structural abnor- malities in LB contents in cathelin-related antimicrobial peptide (CRAMP), the murine homologue of LL-37, knockout mice.60 Recently, proteases have been demon- strated to regulate the antimicrobial activity or inflamma- tory effect of AMPs through proteolytic degradation of these peptides. KLK5 and KLK7 were shown to be co- localized with cathelicidin and to control enzymatic acti- vation of the cathelicidin precursor (hCAP18) and also to influence processing into shorter peptides with alternate biological activity.22 The observation that the epidermal extracts of SPINK5-deficient mice show increased antimi- crobial activity as compared with the controls indicates that the processing of cathelicidin by highly active serine proteases in SPINK5-deficient mice skin augmented antimicrobial activity.22 Recent study has demonstrated that the expression of KLK5 and cathelicidin was up-regulated in the lesional skin of patients with rosacea with altered abundance and the processing of cathelicidin peptides compared to normal individuals.61 It was also suggested that the high levels of abnormally processed cathelicidins observed in rosacea patients are a result of a post-transla- tional processing associated with increased serine protease activity and that these proteolytically processed forms of cathelicidin peptides trigger skin inflammation in rocasea.61 PAR-2- mediated function Permeability barrier homeostasis The involvement of PAR-2 in epidermal permeability barrier homeostasis by mediating signaling from serine proteases in the skin has been recently evidenced.7,11,12 Al- though controversial, recent studies have shown that PAR- 2 localized in the suprabasal layers of mouse and human epidermis with high levels of PAR-2 in the stratum gra- nulosum, suggesting that PAR-2 might act as the primary sensor of barrier-initiated serine protease activity.7,62,63 Acute barrier disruption leads to an increase in SC pH from basal levels of 5.0-5.5 toward a more neutral pH, which, in turn, increases the activity of serine protease, which has an optimal activity at neutral pH.11,64 This inc- rease in serine protease activity activates PAR-2 on kera- tinocytes of SG, resulting in decreased LB secretion and a consequent decrease in the formation of caveolae and lipid raft (Fig. 2).7 It was reported that topical PAR-2 agonist pep- tide significantly delayed barrier recovery and inhibited LB secretion following acute barrier disruption in murine skin, whereas PAR-2 knockout mice showed increased LB secretion and accelerated barrier recovery following acute disruption as compared to wild-type littermates.7 In addi- 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. Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010 813