BACKGROUND Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETARs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch. METHODS In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed. RESULTS CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect. CONCLUSION Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1.

中文翻译：

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小鼠结缔组织肥大细胞蛋白酶类胰蛋白酶和羧肽酶A3在内皮素1引起的瘙痒中起保护作用。

背景技术瘙痒是一种令人不适的感觉，其可能使人衰弱，特别是如果它是慢性的并且是非组织胺能起源的，因为治疗选择有限。内皮素-1（ET-1）是一种有效的内源性血管收缩药，当外源性给药时，它还具有通过激活初级传入内皮素A受体（ETAR）来诱导灼热的非组胺能性瘙痒的能力。ET-1由皮肤中发现的几种细胞类型（包括巨噬细胞和角质形成细胞）内源性释放。肥大细胞表达ETAR，因此可以被ET-1脱粒，并且已知肥大细胞蛋白酶的糜酶和羧肽酶A3（CPA3）分别产生或降解ET-1，表明肥大细胞的蛋白酶在ET的调节中具有作用-1引起的瘙痒。小鼠肥大细胞蛋白酶（mMCP），mMCP4（糜蛋白酶），mMCP6（胰蛋白酶），CPA3和CPA3存在于结缔组织型肥大细胞中，是与人类肥大细胞蛋白酶最接近的功能同源物，但对其在内皮素诱导的瘙痒中的作用知之甚少。方法在这项研究中，我们评估了肥大细胞蛋白酶缺乏对ET-1诱导的scratch抓行为的影响。为了对此进行调查，将mMCP基因敲除小鼠和转基因小鼠皮内注射ET-1，并记录和分析它们的抓挠行为。结果与野生型对照相比，CPA3缺陷型小鼠和缺乏所有三种蛋白酶的小鼠表现出较高的抓挠行为水平。在缺乏mMCP6的小鼠中也发现了挠性发作的次数有适度增加，而缺乏mMCP4的小鼠没有任何作用。结论总而言之，这些发现确定了肥大细胞蛋白酶的重要作用，