Granzyme B in epithelial barrier dysfunction and related skin diseases

The predominant function of the skin is to serve as a barrier-to protect against external insults and to prevent water loss. Junctional and structural proteins in the stratum corneum, the outermost layer of the epidermis, are critical to the integrity of the epidermal barrier as it balances ongoing outward migration, differentiation, and desquamation of keratinocytes in the epidermis. As such, epidermal barrier function is highly susceptible to upsurges of proteolytic activity in the stratum corneum and epidermis. Granzyme B is a serine protease scarce in healthy tissues but present at high levels in tissues encumbered by chronic inflammation. Discovered in the 1980s, granzyme B is currently recognized for its intracellular roles in immune cell-mediated apoptosis as well as extracellular roles in inflammation, chronic injuries, tissue remodeling, as well as processing of cytokines, matrix proteins, and autoantigens. Increasing evidence has emerged in recent years supporting a role for granzyme B in promoting barrier dysfunction in the epidermis by direct cleavage of barrier proteins and eliciting immunoreactivity. Likewise, granzyme B contributes to impaired epithelial function of the airways, retina, gut, and vessels. In the present review, the role of granzyme B in cutaneous epithelial dysfunction is discussed in the context of specific conditions with an overview of underlying mechanisms as well as utility of current experimental and therapeutic inhibitors.