The primary function of the skin epidermis is to protect the organism from external insults and prevent desiccation. To maintain its protective barrier function, old corneocytes skin cells are continuously peeled. The proteolytic degradation of structural and connective proteins through the concerted action of tightly regulated proteases plays a key role in this process.
Of special interest are proteases belonging to the class of kallikreins. Tissue kallikreins (KLKs) form the largest family of human secreted serine proteases encoded by 15 genes clustered on chromosome 19. Several of these KLKs were found in the upper skin layers stratum granulosum and stratum corneum and KLK expression studies strongly suggest their functional involvement in physiological and pathophysiological processes. KLK7, named stratum corneum chymotryptic enzyme (SCCE) and KLK5, the stratum corneum tryptic enzyme (SCTE), were isolated as the main serine proteases expressed in skin. Their involvement in corneocyte shedding is attributed to the cleavage of the structural junction proteins corneodesmosin and desmocollin 1. Recently, multiple other kallikreins beside KLK5 and KLK7 were shown to be expressed in skin and found to be hyperactive in skin diseases.
Regulation of KLK activity plays an important role in multiple skin barrier functions including desquamation, antimicrobial defense, and lipid permeability
Skin proteases including tissue kallikreins are regulated on different levels. Firstly, they are expressed as inactive proform proteins and require activation by proteolytic cleavage. This activation is achieved through a complex interaction of auto- and cross-activation including various kallikreins as well as unrelated proteases. Upon activation the kallikrein proteolytic activities are balanced through the action of serine protease inhibitors, including a protein called LEKTI (Lympho Epithelial Kazal Type Inhibitor). LEKTI is encoded by the SPINK5 gene (Serine Proteinase Inhibitor Kazal type 5).
In skin, protease activity is linked to inflammation via the activation of proteinase-activated receptor (PAR) signaling pathways. Dysregulation of these pathways either due to changed expression or activity of the proteases or their inhibitors was shown in pruritus aspects of various skin disorders including Netherton syndrome, atopic dermatitis or psoriasis.
PAR proteins are receptors, which can be irreversibly activated through proteolysis of the extracellular domain. The PAR family consists of four members, PAR-1 to PAR-4 and growing evidence suggests an implication of PAR-2 in the pro-inflammatory process by upregulating signals as ICAM-1 via the activation of NF-κB and other pathways. PAR-2 has been shown to be activated by skin kallikreins and in atopic dermatitis and Netherton syndrome patients.
Finally, recent studies showed that skin inflammation caused by UVB irradiation is linked to reduced expression of KLK inhibitors and increased proteolytic activity.