Background: Itch is a benign involuntary scratching action which aims to expel noxious materials or pathogens from the skin in response to fastidious stimuli. However, if this protective response persists longer than 6 weeks, it is defined as chronic itch and is highly prevalent in multiple inflammatory skin diseases. Itch is particularly difficult to manage, as it activates the striatum’s reward and motivation centres, leading to an unrelenting itch-scratch cycle that negatively exacerbates the physical and psychological health and quality of life of patients. Globally, at least 7% of the population suffers from chronic itch, which is consistently reported by 87-100% of dermatitis patients, and by 79% of psoriasis patients. Current treatments aimed at treating itch are non-specific and target inflammatory processes. More recent studies have identified a naturally expressed protease called granzyme K, which is elevated in multiple inflammatory skin diseases characterised by persistent itch, including atopic dermatitis and psoriasis. Mechanistically, granzyme K was identified to be involved in a key step of the chronic itch pathway. We therefore hypothesise that granzyme K is involved in chronic itch.
Methods: Itch and pain behaviour was assessed in mice responding to intradermal injection of granzyme K into the cheek. Itch and pain were also assessed in a model of chronic itch, comparing granzyme K inhibitor and vehicle-exposed mice as well as granzyme K knockout compared to wildtype mice. In addition to itch, scratch mediated tissue damage was assessed histologically.
Results: Direct exposure to granzyme K induced a PAR-2-mediated chronic itch response. A single dose of the granzyme K inhibitory drug applied topically led to >80% reduction for up to 5 hours in itch-scratching behaviour, reduced skin damage and overall improvement of skin health.
Conclusion: Based on these data, granzyme K contributes to chronic itch whilst inhibition may circumvent the itch-scratch cycle.