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

Q2 Medicine
Keshi Chung , Thomas Pitcher , Andrew D. Grant , Ellen Hewitt , Erik Lindstrom , Marzia Malcangio
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引用次数: 21

摘要

慢性瘙痒是一种以过度抓挠为特征的衰弱状态,是特应性皮炎等皮肤病中经常报道的症状。有人提出,皮肤角质形成细胞或驻留或浸润皮肤的免疫细胞释放的半胱氨酸蛋白酶组织蛋白酶S (CatS)可能在慢性瘙痒条件下起搔痒原的作用。已知cat可激活蛋白酶激活受体2 (PAR2)。因此,我们假设cat对神经元表达的PAR2的酶促激活是感觉神经元激活和瘙痒信号传递的原因。皮内注射人重组(hr)-CatS或PAR2激动剂SLIGRL-NH2,通过引起小鼠的抓痕行为表现为搔痒原。与野生型小鼠相比,cat抑制剂和PAR2拮抗剂可以阻止hr -CatS诱导的抓痕行为,TRPV1 - / -小鼠的抓痕行为减少了50%,而TRPA1 - / -小鼠的抓痕行为没有显著减少。培养的背根神经节(DRG)细胞在与hr-CatS孵育后显示[Ca2+]i增加,并且在PAR2拮抗剂存在或TRPV1 - / -小鼠的神经元培养中,对hr-CatS有反应的神经元百分比下降。综上所述,我们的研究结果表明,cat通过在表达trpv1的感觉神经元中激活PAR2而发挥瘙痒原的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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

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.

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来源期刊
Neurobiology of Pain
Neurobiology of Pain Medicine-Anesthesiology and Pain Medicine
CiteScore
4.40
自引率
0.00%
发文量
29
审稿时长
54 days
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