Physiological and pathological roles of kallikrein-related peptidases in the epidermis

Identifying the function of kallikrein-related peptidases (KLKs) in the epidermis has elicited great interest over recent decades. KLKs comprise 15 serine proteases, and their activities are regulated by complex and fine-tuned mechanisms involving the proteolytic activation cascade, endogenous inhibitors, and environmental factors. When the balance is disrupted, excessive or insufficient protease activity can impair epidermal barrier homeostasis. KLKs are involved in various events, such as skin inflammation, wound healing, pruritus, anti-bacterial activity, and viral susceptibility. One of the primary roles of KLKs, mainly KLK5 and KLK7, is physiological desquamation. Both proteases are also involved in the development of inflammatory skin diseases with barrier abnormalities, e.g., Netherton syndrome and atopic dermatitis (AD). In Netherton syndrome, unrestricted activity of KLK5 due to loss of the major endogenous inhibitor, lymphoepithelial Kazal-type-related inhibitor (LEKTI), destroys the component molecules of corneodesmosome, leading to Th2 and Th17 inflammation. Meanwhile, the increased activity of KLK7 in the hyperkeratotic lesions of chronic AD is suppressed by upregulated LEKTI. The functions and implications of other KLKs including KLK6 and KLK8 in healthy and diseased skin such as psoriasis represent an exciting but relatively unexplored area. Clarifying the function of epidermal KLKs will enable development of disease-specific biomarkers and new therapeutic strategies.