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Papers of the Week

Papers: 22 Jun 2019 - 28 Jun 2019

Animal Studies


2019 Aug-Dec

Neurobiol Pain


Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour.


Chung K, Pitcher T, Grant AD, Hewitt E, Lindstrom E, Malcangio M
Neurobiol Pain. 2019 Aug-Dec; 6:100032.
PMID: 31223140.


Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1 mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1 mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca] following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1 mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.