Role of proteinase‐activated receptors (PARs) during cutaneous inflammation and the immune response

Abstract

Proteinase‐activated receptors constitute a new subfamily of G protein‐coupled receptors with seven transmembrane domains which are activated by various exogenous or endogenous serine proteinases such as thrombin, cathepsin G, trypsins, tryptase, clotting factors (VV, Xa), bacterial proteases or mite antigens. In addition, PAR1 can be activated by MMP‐1. Recent knowledge indicate that proteases are not merely enzymes which cleave proteins in the extracellular space, but are signaling molecules involved in many processes by activating specific receptors in an autocrine, paracrine and endocrine fashion. MMP‐1 activates PAR1 and is thereby involved in the migration and invasive potential of melanoma cells. PAR2 is a receptor for mast cell tryptase or house dust mite allergens which is released during inflammation and allergic reactions. In the skin, PAR2 is diversly expressed by keratinocytes, endothelial cells and occasionally on sensory nerves of human skin in various disease states. Moreover, immunocompetent cells such as mast cells and neutrophils express functional PAR2 thereby contributing to inflammation and host defense. Own data revealed that PAR2 contributes to neurogenic inflammation by releasing neuropeptides from sensory nerves resulting in edema, plasma extravasation and infiltration of neutrophils. Thus, mast cells may communicate with sensory nerves in inflammatory tissues by activating PAR2 via tryptase. Vice versa, PAR2 activation of cutaneous mast cells leads to a release of histamine suggesting a bidirectional pathway of mast cell–nerve communication. Moreover, PAR2 agonists up‐regulate expression of certain cell adhesion molecules and cytokines such as interleukin‐6 and interleukin‐8 on dermal microvascular endothelial cells or regulate neutrophil migration or integrin expression – a role of PAR2 in leukocyte/endothelial interactions. These effects may be partly mediated by NF‐κB, an important transcription factor during inflammation and immune response. PAR2 stimulation results in the activation of NF‐κB on microvascular endothelial cells and keratinocytes thereby regulating ICAM‐1 expression. We also demonstrate evidence for a diverse expression of PAR2 in various skin diseases and highlight the recent knowledge about the important role of PAR2 during inflammation and the immune response. Together, PAR2‐modulating agents may be new tools for the treatment of inflammatory and allergic diseases in the skin.