Role of protease‐activated receptor‐2 during cutaneous inflam‐mation and the immune response

Protease‐activated receptors (PARs) constitute a new subfamily of G‐protein‐coupled receptors with seven transmembrane domains which are activated by various serine proteases such as thrombin, cathepsin G, trypsin or tryptase, and bacterial proteases or mite antigens, for example. PAR 2 is a receptor for mast cell tryptase or house dust mite allergens, which is released during inflammation and allergic reactions. In the skin, PAR 2 is diversely expressed by keratinocytes, endothelial cells, and occasionally sensory nerves of human skin in various disease states. Moreover, immunocompetent cells such as T cells and neutrophils express functional PAR 2 , thereby contributing to inflammation and host defense. Own data revealed that PAR 2 contributes to neurogenic inflammation by releasing neuropeptides from sensory nerves resulting in oedema, plasma extravasation and infiltration of neutrophils. Thus, mast cells may communicate with sensory nerves in inflammatory tissues by activating PAR 2 via tryptase. Moreover, PAR 2 agonists upregulate the expression of certain cell‐adhesion molecules and cytokines such as interleukin‐6 and interleukin‐8 on dermal microvascular endothelial cells or regulate neutrophil migration, indicating that PAR 2 plays an important role in leucocyte/endothelial interactions. These effects may be partly mediated by NF‐κB, an important transcription factor during inflammation and immune response. PAR 2 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 PAR 2 in various skin diseases and highlight the recent knowledge about the important role of PAR 2 during inflammation and the immune response. Together, PAR 2 ‐modulating agents may be new tools for the treatment of inflammatory and allergic diseases in the skin.