Keshi Chung , Thomas Pitcher , Andrew D. Grant , Ellen Hewitt , Erik Lindstrom , Marzia Malcangio
{"title":"组织蛋白酶S通过蛋白酶激活受体2激活感觉神经元并诱导瘙痒样行为","authors":"Keshi Chung , Thomas Pitcher , Andrew D. Grant , Ellen Hewitt , Erik Lindstrom , Marzia Malcangio","doi":"10.1016/j.ynpai.2019.100032","DOIUrl":null,"url":null,"abstract":"<div><p>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<sub>2</sub> 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<sup>−/−</sup> mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1<sup>−/−</sup> mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca<sup>2+</sup>]<sub>i</sub> 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<sup>−/−</sup> mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.</p></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"6 ","pages":"Article 100032"},"PeriodicalIF":0.0000,"publicationDate":"2019-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ynpai.2019.100032","citationCount":"21","resultStr":"{\"title\":\"Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour\",\"authors\":\"Keshi Chung , Thomas Pitcher , Andrew D. Grant , Ellen Hewitt , Erik Lindstrom , Marzia Malcangio\",\"doi\":\"10.1016/j.ynpai.2019.100032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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<sub>2</sub> 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<sup>−/−</sup> mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1<sup>−/−</sup> mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca<sup>2+</sup>]<sub>i</sub> 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<sup>−/−</sup> mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.</p></div>\",\"PeriodicalId\":52177,\"journal\":{\"name\":\"Neurobiology of Pain\",\"volume\":\"6 \",\"pages\":\"Article 100032\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2019-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/j.ynpai.2019.100032\",\"citationCount\":\"21\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Pain\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2452073X19300054\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Pain","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2452073X19300054","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour
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-NH2 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 [Ca2+]i 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.