Oral Presentation 9th General Meeting of the International Proteolysis Society 2015

Granzyme B in aging, extracellular matrix remodelling and impaired healing (#2)

Leigh G Parkinson 1 , Hongyan Zhao 1 , Paul R Hiebert 1 , David J Granville 1
  1. University of British Columbia, Vancouver, BC, Canada
The role of the serine protease, Granzyme B (GzmB), in cytotoxic lymphocyte-mediated apoptosis is well-documented. However, in recent years, other roles for GzmB in inflammation, vascular permeability, and extracellular matrix degradation have been reported. It is now recognized that GzmB can be expressed in other types of immune and non-immune cells that are not capable of forming immunological synapses and/or do not express perforin, the pore-forming molecule that facilitates GzmB internalization and subsequent apoptosis. In several conditions associated with aberrant inflammation, impaired healing and aging, GzmB accumulates in the extracellular milieu and may contribute to pathogenesis through the cleavage of extracellular proteins. In support, extracellular GzmB inhibition improves re-epithelialization and remodelling in murine models of age-impaired and diabetic wound healing. Previous studies demonstrated that ultraviolet light (UV) induces GzmB expression in isolated human keratinocytes in culture, and in ex-vivo human skin punch biopsies. In the present study, a custom made solar-simulated light box was used to assess the role of GzmB in UV-induced skin aging in mice. UV irradiation induced GzmB expression in keratinocytes and caused an increase in GzmB-positive mast cells. The absence of GzmB resulted in reduced skin aging,and significantly protected against the loss of dermal collagen density and decorin. Further studies determined that GzmB-mediated cleavage of decorin rendered collagen more susceptible to MMP-mediated degradation, while GzmB-mediated cleavage of E-cadherin contributed to reduced epithelial barrier function. In summary, our studies suggest that increased extracellular GzmB contributes to skin aging and disease through processes involving the cleavage of extracellular matrix and epithelial junction proteins.