Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV
Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV
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DOI：
10.1016/j.jaci.2021.08.003
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发表时间：
2022-03-03
影响因子：
14.2
通讯作者：
Takamori, Kenji
中科院分区：
文献类型：
--
作者：
Komiya, Eriko;Tominaga, Mitsutoshi;Takamori, Kenji
背景：机械性异位（或无害的机械性刺激引起的瘙痒）常发生在干燥性皮肤疾病中，如特应性皮炎和牛皮癣。然而，机械变形的分子和细胞机制尚不清楚。我们最近报道了CD26参与银屑病瘙痒的调节。该分子具有二肽基肽酶IV （DPPIV）酶活性，并通过加工包括神经肽在内的各种物质发挥其生物效应。目的：研究CD26/ DPPIV基因敲除（CD26KO）小鼠机械异位的外周机制。方法：对CD26KO小鼠和野生型小鼠进行无害化机械刺激。抓挠反应的总次数作为异变得分。然后进行免疫组织化学和行为药理学分析，以检测CD26/DPPIV或内源性mu-阿片受体激动剂内源性内啡肽（EMs）的生理活性。结果：与野生型小鼠相比，CD26KO小鼠出现机械异位的频率更高。皮内给药重组DPPIV或外周mua -阿片受体拮抗剂纳洛酮可显著降低CD26KO小鼠的异变评分，但没有酶活性的突变DPPIV则没有。em （EM-1和EM-2）是mu-阿片受体的选择性配体，是DPPIV的底物。免疫组织化学结果显示，上皮细胞位于角质形成细胞、成纤维细胞和周围感觉神经中。行为学分析显示，相对于化学瘙痒，EMs更倾向于引起机械异动。dppiv消化形式的EMs不诱导机械异位。结论：在CD26/DPPIV的酶促作用下，EMs可诱导外周细胞发生机械异位。
Background: Mechanical alloknesis (or innocuous mechanical stimuli-evoked itch) often occurs in dry skin-based disorders such as atopic dermatitis and psoriasis. However, the molecular and cellular mechanisms underlying mechanical alloknesis remain unclear. We recently reported the involvement of CD26 in the regulation of psoriatic itch. This molecule exhibits dipeptidyl peptidase IV (DPPIV) enzyme activity and exerts its biologic effects by processing various substances, including neuropeptides.Objective: The aim of the present study was to investigate the peripheral mechanisms of mechanical alloknesis by using CD26/ DPPIV knockout (CD26KO) mice.Methods: We applied innocuous mechanical stimuli to CD26KO or wild-type mice. The total number of scratching responses was counted as the alloknesis score. Immunohistochemical and behavioral pharmacologic analyses were then performed to examine the physiologic activities of CD26/DPPIV or endomorphins (EMs), endogenous agonists of mu-opioid receptors.Results: Mechanical alloknesis was more frequent in CD26KO mice than in wild-type mice. The alloknesis score in CD26KO mice was significantly reduced by the intradermal administration of recombinant DPPIV or naloxone methiodide, a peripheral mu-opioid receptor antagonist, but not by that of mutant DPPIV without enzyme activity. EMs (EM-1 and EM-2), selective ligands for mu-opioid receptors, are substrates for DPPIV. Immunohistochemically, EMs were located in keratinocytes, fibroblasts, and peripheral sensory nerves. Behavioral analyses revealed that EMs preferentially provoked mechanical alloknesis over chemical itch. DPPIV-digested forms of EMs did not induce mechanical alloknesis.Conclusion: The present results suggest that EMs induce mechanical alloknesis at the periphery under the enzymatic control of CD26/DPPIV.