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A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
Published on: November 28, 2014
Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation
Christopher T Turner1,2, Matthew R Zeglinski1,2, Wendy Boivin2
1International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
Background:
Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while abundant in inflamed tissues. Initially thought to play an exclusive role in immune-mediated cell death, extracellular GzmK can also promote inflammation.
Objectives:
To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease.
Methods:
A panel of human AD and control samples was analysed to determine if GzmK is elevated. Next, to determine a pathological role for GzmK in AD-like skin inflammation, oxazolone-induced dermatitis was induced in GzmK-/- and wild-type (WT) mice.
Results:
In human lesional AD samples, there was an increase in the number of GzmK+ cells compared with healthy controls. GzmK-/- mice exhibited reduced overall disease severity characterized by reductions in scaling, erosions and erythema. Surprisingly, the presence of GzmK did not notably increase the overall pro-inflammatory response or epidermal barrier permeability in WT mice; rather, GzmK impaired angiogenesis, increased microvascular damage and microhaemorrhage. Mechanistically, GzmK contributed to vessel damage through cleavage of syndecan-1, a key structural component of the glycocalyx, which coats the luminal surface of vascular endothelia.
Conclusions:
GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.
Insights
Granzyme K (GzmK) is elevated in atopic dermatitis (AD) skin. While not increasing inflammation, GzmK impairs blood vessel formation and causes damage by cleaving syndecan-1, suggesting it as a therapeutic target.
Area of Science:
- Immunology
- Dermatology
- Vascular Biology
Background:
- Granzyme K (GzmK) is a serine protease found in inflamed tissues, implicated in inflammation and cell death.
- Its role in inflammatory skin diseases like atopic dermatitis (AD) is not fully understood.
Purpose of the Study:
- To investigate the role of Granzyme K (GzmK) in the pathogenesis of atopic dermatitis (AD).
- To determine if GzmK levels are elevated in human AD skin and if it contributes to AD-like skin inflammation in mice.
Main Methods:
- Analysis of human lesional AD samples and healthy controls for GzmK+ cell presence.
- Induction of oxazolone-induced dermatitis in GzmK knockout (GzmK-/-) and wild-type (WT) mice.
Main Results:
- Human AD skin showed increased GzmK+ cells compared to controls.
- GzmK-/- mice exhibited reduced AD-like skin inflammation severity.
- GzmK impaired angiogenesis and increased microvascular damage/hemorrhage by cleaving syndecan-1.
Conclusions:
- GzmK plays a pathological role in AD by damaging blood vessels.
- GzmK is a potential therapeutic target for inflammatory skin conditions, vasculitis, and pathological angiogenesis.
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