Proteases and proteomics: Cutting to the core of human skin pathologies

Abstract

Preserving the integrity of the skin's outermost layer (the epidermis) is vital for humans to thrive in hostile surroundings. Covering the entire body, the epidermis forms a thin but impenetrable cellular cordon that repels external assaults and blocks escape of water and electrolytes from within. This structure exists in a perpetual state of regeneration where the production of new cellular subunits at the base of the epidermis is offset by the release of terminally differentiated corneocytes from the surface. It is becoming increasingly clear that proteases hold vital roles in assembling and maintaining the epidermal barrier. More than 30 proteases are expressed by keratinocytes or infiltrating immune cells and the activity of each must be maintained within narrow limits and confined to the correct time and place. Accordingly, over- or under-exertion of proteolytic activity is a common factor in a multitude of skin disorders that range in severity from relatively mild to life-threatening. This review explores the current state of knowledge on the involvement of proteases in skin diseases and the latest findings from proteomic and transcriptomic studies focused on uncovering novel (patho)physiological roles for these enzymes.

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

“…The pathophysiology of palmoplantar hyperkeratosis in PLS patients has not been confirmed. It has been hypothesized that NSPs play a crucial role in epidermal barrier function, and that imbalance in proteolytic activity may cause various skin disorders such as redness and scaling . However, as suggested by Miller et al ., an alternative explanation for the skin events may be that DPP1 also plays an important role in maintaining the structural integrity of plantar and palmar epidermal surfaces, by contributing to the processing of keratins .…”

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

“…2). 30 The rat epidermis has approximately 10 times more proteolytic activity as compared to the dermis, and proteolytic enzymes are found in the epidermal cells. In the case of dermis, proteolytic enzymes are present in the infiltrating immune cells, sebaceous glands, and follicular cells.…”

“…24 The cutaneous surface of normal adult humans has around 20 billion T lymphocyte cells, which can secrete proteolytic enzymes leading to degradation of the administered TPs. 30,32 The proteolytic enzymes such as tryptase, cathepsin G, neutrophil elastase originate from the T cells and other infiltrating immune cells. 30 Caspase-14 is a major cysteine protease, expressed in the human epidermal keratinocytes.…”

“…30,32 The proteolytic enzymes such as tryptase, cathepsin G, neutrophil elastase originate from the T cells and other infiltrating immune cells. 30 Caspase-14 is a major cysteine protease, expressed in the human epidermal keratinocytes. Serine protease HtrA1 is found ubiquitously in many organs; but increased amounts are found in the mature layers of the epidermis.…”

Expression of the Ly6/uPAR-Domain Proteins C4.4A and Haldisin in Non-Invasive and Invasive Skin Lesions

“…Homeostasis of this exquisitely ordered organ is fuelled by different resident stem cells that enable constitutive renewal of the stratified squamous epithelium as well as its various epidermal appendages (Blanpain and Fuchs 2009). The integrity of this physical barrier function is, however, occasionally compromised by congenital dysregulation of, for example, cytokeratins (Coulombe et al 2009), proteases (de Veer et al 2014;Sales et al 2010) and ion pumps (Sakuntabhai et al 1999). In addition, certain autoimmune diseases targeting such antigens also perturb skin homeostasis (Nishie 2014;Stanley and Amagai 2006) and the subsequent pathogenesis (e.g., severity of blister formation) may be further exacerbated by local plasminogen activation (Liu et al 2005).…”