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KMID : 0984920090110020080
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Journal of Skin Barrier Research
2009 Volume.11 No. 2 p.80 ~ p.103
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Protease-Activated Receptors-2: Role in Skin Biology and Barrier Function
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Ferda Cevikbas
Akihiko Ikoma
Martin Steinhoff
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Abstract
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Proteinases play an essential role in skin homeostasis and various disease states. This is ? at least in part ? mediated via activation of proteinase-activated receptors (PARs). These are G-protein?coupled receptors with seven transmembrane domains that are activated by specific proteolytic cleavage of the extracellular N-terminus. To date, four PARs are cloned and characterized (PAR1?4). They are stimulated by a variety of serine proteinases. PAR1, PAR3 and PAR4 are cleaved by thrombin, for example. Both PAR1 and PAR4 can be activated by trypsin as well; PAR4 can be also activated by cathepsin G and PAR1 can also be triggered by matrix metalloproteinase-1. PAR2 can be activated by a variety of endogenous serine proteinases like tryptase, matriptase or certain kallikreins. The latter have an important impact in the regulation of skin barrier and may thus be involved in its malfunction during disease state. This receptor can additionally be stimulated by various exogenous proteinases produced by pathogenic organisms like mites, bacteria or fungi, which are capable of modulating epidermal barrier function. It can also be inactivated by certain proteinases which may be of pathophysiological releavance; these mechanisms, however, are poorly understood as of yet. PAR2 is expressed
by many cell types present in the skin including keratinocytes in the higher epidermal layers, fibroblasts, endothelial cells as well as by sensory neurons. Moreover, functional PAR2 is expressed by cells crucially involved in innate and adaptive immunity such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells, which may affect skin barrier function during inflammation and immune responses. Activation of the receptor leads to the production of various cytokines, chemokines or growth factors thereby modulating skin homeostasis, barrier function, immune and inflammatory responses as well as tumor surveillance. Thus, aiming at proteases and PARs may be beneficial for the treatrment of various skin diseases and barrier dysfunction.
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KEYWORD
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G protein-coupled receptors, Proteases, Skin barrier, Inflammation, Therapy
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