DOI 10.3349/ymj.2010.51.6.808 Review Article pISSN: 0513-5796, eISSN: 1976-2437 Yonsei Med J 51(6):808-822, 2010 Protease and Protease-Activated Receptor-2 Signaling in the Pathogenesis of Atopic Dermatitis Sang Eun Lee,1,2 Se Kyoo Jeong,3 and Seung Hun Lee1,2 1Department of Dermatology, 2Human Barrier Research Institute, Yonsei University College of Medicine, Seoul; 3Research Division, NeoPharm Co., Ltd., Daejeon, Korea. Received: August 17, 2010 Proteases in the skin are essential to epidermal permeability barrier homeostasis. Corresponding author: Dr. Seung Hun Lee, In addition to their direct proteolytic effects, certain proteases signal to cells by Department of Dermatology, activating protease-activated receptors (PARs), the G-protein-coupled receptors. Yonsei University College of Medicine, The expression of functional PAR-2 on human skin and its role in inflammation, Gangnam Severance Hospital, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis 712 Eonju-ro, Gangnam-gu, (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier Seoul 135-720, Korea. defects and allergic inflammation, which is sustained by gene-environmental Tel: 82-2-2019-3361, Fax: 82-2-3463-6136 interactions. Recent studies have revealed aberrant expression and activation of E-mail: [email protected] 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 ∙The authors have no financial conflicts of protease/protease inhibitor encoding genes, increase in skin surface pH, and interest. 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. Key Words: Atopic dermatitis, protease, protease-activated receptor-2 (PAR-2) INTRODUCTION Proteases are now considered not only to be enzymes that conduct hydrolysis of © Copyright: peptide bonds linking amino acids, but also signaling molecules that play an Yonsei University College of Medicine 2010 important role in homeostatic regulation in mammals and numerous pathological This is an Open Access article distributed under the 1,2 terms of the Creative Commons Attribution Non- conditions. In the skin, three families of proteases have been found in the stratum Commercial License (http://creativecommons.org/ corneum (SC), including the epidermal specific serine proteases, kallikrein 5 (SC licenses/by-nc/3.0) which permits unrestricted non- tryptic enzyme, SCTE) and kallikrein 7 (SC chymotryptic enzyme, SCCE), as commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. well as cysteine proteases, including cathepsin C, L, and V (SC thiol protease), 808 Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010 Protease/PAR-2 Signaling in Atopic Dermatitis and at least one aspartate protease, cathepsin D.3-7 These these pro-KLK zymogens are activated through a KLK proteases are tightly regulated by specific protease inhibi- proteolytic activation cascade.26 KLK5 can be activated by tors and mediate various cellular responses in the skin, itself or by KLK14 and then activate several other pro- such as inflammation and immune responses, host defense, KLKs; therefore KLK5 is thought to be the key protease chemotaxis, cytokine expression, vascular function, tissue for the initiation of the KLK cascade.24 Significantly, KLK5 repair, and apoptosis.8 In addition to endogenous proteases, and KLK14 are known to activate PAR-2, thereby modulat- exogenous proteases from allergens such as house dust ing epidermal permeability barrier homeostasis, immune mites, cockroaches, certain bacteria, and fungi can also and inflammatory responses, skin pigmentation, itching signal the epidermis. A number of biological activities of sensations, as well as tumor surveillance.10,27 KLK8 has proteases are mediated, at least in part, by the activation of been reported to be localized in the LBs with KLK5, KLK7 its receptors, protease-activated receptors (PARs).9 Recent and their inhibitors and secreted in the SG-SC interface, works have indicated that PAR-2, as a sensor for endoge- regulating desquamation and epidermal proliferation.28,29 nous as well as exogenous proteases, plays numerous Recent studies have investigated factors regulating the physiological and pathophysiological roles in the skin.8,10 In expression of KLKs in the skin and reported that epider- addition, there is increasing evidence that protease and mal calcium ions, vitamin D3, and retinoic acid indepen- PAR-2 play an important role in the maintenance of epi- dently regulate the expression of KLK5 and KLK7 in dermal permeability barrier homeostasis.7,11,12 Moreover, normal human epidermal keratinocytes.30 An increase in abnormal expression or activity of serine proteases and extracellular calcium induced KLK5 and KLK7 expres- PAR-2 has been associated with several inflammatory skin sion with induction of differentiation markers, suggesting disorders involving barrier abnormalities, including atopic that the expression of KLKs is induced during epidermal dermatitis, netherton syndrome (NS), psoriasis, and differentiation. In contrast, both 9-cis retinoic acid and 13- peeling skin syndrome.13-18 In this review, we will discuss cis retinoic acid increased KLK5 and KLK7 expression, the role of protease/PAR-2 signaling in epidermal permea- independently of keratinocyte differentiation. 1,25 (OH)2 bility barrier homeostasis, as well as its contribution to the vitamin D3, which is well known to induce cathelicidin pathogenesis of atopic dermatitis (AD). expression, was also demonstrated to stimulate the expres- sion of KLK5 and KLK7, which are co-localized with cathelicidin. SERINE PROTEASES AND THEIR In addition to KLKs, the two transmembrane serine INHIBITORS IN SKIN protease, matriptase (MT-SP1) and prostasin have been identified in the uppermost epidermal layers and postulated Human tissue kallikreins (KLKs) are the largest family of to be involved in epidermal barrier formation and SC hydra- trypsin- or chymotrypsin-like secreted serine proteases.13 tion via epithelial sodium channel-induced intracellular Eight KLKs, including KLK5, -6, -7, -8, -10, -11, -13, and calcium influx and consequent activation of calcium- -14 are known to be expressed in the epidermis and skin dependent proteases and transglutaminases (TGMs).31 appendages, such as sebaceous gland.19 Among these, only Moreover, the observation that mice deleted for matriptase KLK7 exhibits chymotrypsin-like substrate specificity; the showed impaired desquamation suggests that matriptase is other KLKs exhibit trypsin-like serine proteases. It is well also involved in the process of desquamation.32 known that KLK5 and KLK7 are the major active KLKs A number of serine protease inhibitors are present in the in the SC, regulating the desquamation process through skin, and regulate proteolytic activity in order to prevent corneodesmosomal cleavage and lipid barrier formation by excessive serine protease cascade, while also maintaining degrading lipid processing enzymes.19-21 In addition, KLK5 permeability barrier homeostasis. Among several serine and KLK7 have been shown to control the enzymatic protease inhibitors observed in the SC, such as secretory processing of cathelicidin, thereby affecting its antimicro- leucocyte protease inhibitor (SLPI), elafin skin-dericed bial activity and inflammatory responses.22 KLK14 has also antileukoproteinase (SKALP), and plasminogen activator been detected in its active form in the SC and is thought to inhibitor type 2, which are normally cross-linked to the be a candidate protease involved in the process of desqua- cornified envelope, LEKTI-1, a secreted serine protease in- mation, however, its precise role has not been elucidat- hibitor, is thought to be the major player in the SC. LEKTI ed.23,24 KLK5 and KLK7 are stored in the form of pro- is encoded by SPINK5 (serine protease inhibitor Kazal- enzyme in the lamellar bodies (LBs) along with a substrate type 5) and its multidomains exhibit diverse inhibitory of KLK7, corneodesmosin and their inhibitor, lymphoe- effects toward trypsin, plasmin, subtilisin A, cathepsin G, pithelial Kazal-type-related inhibitor (LEKTI).25 Upon and human neutrophil elastase.33 In addition, previous in release into the stratum granulosum (SG)-SC interface, vitro studies demonstrated that LEKTI fragments could Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010 809 Sang Eun Lee, et al. inhibit KLK5, -6, -7, -13, and -14.31 LEKTI-1 is stored in proteolytic cleavage of their extracellular domains.39 Until specific intracellular