Cathepsin S and protease activated receptor-2

: new players in the sensation of itch

Abstract

Whilst acute itch is a beneficial sensation that serves to remove irritants and potentially harmful agents from the skin by eliciting a scratch reflex, chronic itch is a debilitating condition associated with a reduction in quality of life and the development of skin lesions that risk becoming infected. Moreover, few effective treatments exist for chronic itch conditions, particularly those associated with skin diseases such as atopic dermatitis. 
Cathepsin S is a protease that has recently been demonstrated to be involved in pruritus. Preliminary work in our lab demonstrated that intradermal injection of Cathepsin S results in scratching behaviour in mice, while others have found that over-expression of Cathepsin S results in the development of atopic dermatitis-like conditions. However, the source of Cathepsin S in itch conditions, whether Cathepsin S directly activates sensory neurons and the receptors on which it acts to mediate its effects, and whether it causes the release of neurotransmitters from primary afferent fibres had not been addressed. We thus sought to further investigate Cathepsin S-mediated itch. 
We found that skin keratinocytes are a potential source of Cathepsin S, expression of which is upregulated in inflammatory conditions similar to those found in atopic dermatitis. Furthermore, Cathepsin S can be released from these cells following stimulation of TRPV4, and propose that alterations in skin hydration and pH in conditions such as atopic dermatitis might result in increased activity of this channel and hence release of Cathepsin S. We established that Cathepsin S activates sensory neurons in vitro via protease activated receptor 2 (PAR2) and that Cathepsin S-responding neurons belonged to the TRPV1/TRPA1-expressing subset of neurons. Finally, we found that intraplantar Cathepsin S injection results in activation of neurons in the outer laminae of the dorsal horn of the spinal cord, although we could not demonstrate the occurrence of release of neurotransmitters or neuropeptides from the central terminals of primary afferent neurons. 
In conclusion, we have identified a pathway for Cathepsin S-induced itch as release of this protease from keratinocytes activates TRPV1/TRPA1-expressing neurons via PAR2 activation, and engages neurons in the dorsal horn that likely comprise part of the central itch circuitry.

Date of Award	1 Jan 2020
Original language	English
Awarding Institution	King's College London
Supervisor	Marzia Malcangio (Supervisor) & Andrew Grant (Supervisor)