House dust mite allergens induce interleukin 33 (IL-33) synthesis and release from keratinocytes via ATP-mediated extracellular signaling
House dust mite allergens induce interleukin 33 (IL-33) synthesis and release from keratinocytes via ATP-mediated extracellular signaling
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屋尘螨过敏原通过atp介导的细胞外信号传导诱导白细胞介素33 （IL-33）的合成和释放
DOI：
10.1016/j.bbadis.2020.165719
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发表时间：
2020-05-01
影响因子：
6.2
通讯作者：
Sayama, Koji
中科院分区：
文献类型：
--
作者：
Dai, Xiuju;Tohyama, Mikiko;Sayama, Koji
在特应性疾病中，上皮细胞释放细胞因子和趋化因子，引发皮肤炎症。特应性皮炎（AD）的特征是表皮屏障被破坏，可由环境刺激如屋尘螨（HDM）过敏原触发或加重。促炎细胞因子白细胞介素33 （IL-33）在AD的发病机制中起重要作用，但HDM如何激发角质形成细胞中IL-33的产生尚不清楚。为此，我们在此用翼状棘球蚴HDM提取物刺激单层培养的人角质形成细胞和人活皮肤等量物，以研究其对角质形成细胞产生IL-33的影响。HDM提取物诱导细胞内IL-33的表达并调节其加工和成熟，触发角质形成细胞快速释放IL-33。1组HDM过敏原诱导IL-33产生，而2组HDM过敏原不诱导IL-33产生。角质细胞培养上清的ATP分析显示，HDM提取物刺激后，细胞外ATP立即出现急性和短暂的积累。利用广谱P2拮抗剂苏拉明、特异性嘌呤能受体P2Y2 （P2RY2）拮抗剂AR-C118925XX和P2RY2特异性siRNA，我们发现HDM提取物诱导的IL-33表达主要依赖于细胞外ATP/P2Y2信号通路，通过表皮生长因子受体的转激活介导，随后激活ERK激酶信号通路。此外，HDM提取物诱导角质形成细胞释放25 kda IL-33依赖于细胞外ATP/P2信号介导的细胞内Ca2+增加。我们的研究证明了HDM过敏原控制角化细胞产生的il - 33诱导和成熟的新机制，这一先天免疫过程可能在AD的发展或严重程度中发挥作用。
In atopic diseases, the epithelium releases cytokines and chemokines that initiate skin inflammation. Atopic dermatitis (AD) is characterized by a disrupted epidermal barrier and is triggered or exacerbated by environmental stimuli such as house dust mite (HDM) allergens. The proinflammatory cytokine interleukin 33 (IL-33) plays an important role in the pathogenesis of AD, but how IL-33 production in keratinocytes is elicited by HDM is unknown. To that end, here we stimulated monolayer-cultured human keratinocytes and human living skin equivalents with Dermatophagoides pteronyssinus HDM extract to investigate its effects on IL-33 production from keratinocytes. The HDM extract induced intracellular expression of IL-33 and modulated its processing and maturation, triggering rapid IL-33 release from keratinocytes. Group 1 HDM allergen but not group 2 HDM allergen elicited IL-33 production. An ATP assay of keratinocyte culture supernatants revealed an acute and transient accumulation of extracellular ATP immediately after the HDM extract stimulation. Using the broadspectrum P2 antagonist suramin, the specific purinergic receptor P2Y2 (P2RY2) antagonist AR-C118925XX, and P2RY2-specific siRNA, we discovered that the HDM extract-induced IL-33 expression was mainly dependent on extracellular ATP/P2Y2 signaling mediated by transactivation of epidermal growth factor receptor, followed by activation of the ERK kinase signaling pathway. Moreover, HDM extract-induced release of 25-kDa IL-33 from the keratinocytes depended on an extracellular ATP/P2 signaling-mediated intracellular Ca2+ increase. Our study demonstrates the new mechanism controlling the induction and maturation of keratinocyte-produced IL33 by HDM allergens, an innate immune process that might play a role in AD development or severity.