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.