ERK活动的时空集群协调细胞因子诱导的人类气道上皮细胞炎症反应

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nicholaus L DeCuzzi, Daniel Oberbauer, Kenneth J Chmiel, Michael Pargett, Justa M Ferguson, Devan Murphy, Marion Hardy, Abhineet Ram, Amir A Zeki, John G Albeck
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引用次数: 0

摘要

空间协调的 ERK 信号事件("SPREADs")通过表皮生长因子受体和其他受体的分泌配体从中心点向邻近细胞进行辐射传输。SPREADs 可维持非肺部上皮细胞的平衡,但它们是否在气道上皮细胞中发挥作用或在炎症性疾病中失调尚不清楚。为了解决这些问题,我们使用活细胞ERK生物传感器测量了人支气管上皮细胞系(HBE1和16HBE)和原代人支气管上皮细胞(pHBE)在浸没和双相气液界面(ALI)培养条件下(即分化细胞)的SPREAD活性。气道上皮细胞暴露于与哮喘和慢性阻塞性肺病(COPD)相关的促炎细胞因子。1 型促炎细胞因子显著增加了 SPREADs 的频率,这与分化 pHBE 细胞的上皮屏障破坏相吻合。此外,SPREADs与IL-6肽分泌和局部磷-STAT3免疫荧光群的出现相关。为了探究SPREADs的机制,细胞与药物治疗(吉非替尼、替西珠单抗、氢化可的松)或代谢调节剂(胰岛素、2-脱氧葡萄糖)共同处理。氢化可的松、受体信号转导抑制剂和代谢功能抑制剂可减少 SPREAD 的发生,这意味着促炎细胞因子和葡萄糖代谢可通过分泌的表皮生长因子受体和 IL6R 配体调节人气道上皮细胞中的 SPREAD。我们的结论是,时空 ERK 信号在气道上皮细胞炎症期间的屏障稳态和功能障碍中发挥作用。临床上可以利用这种新型信号机制来辅助皮质类固醇治疗哮喘和慢性阻塞性肺病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.

Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. To address these questions, we measured SPREAD activity with live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial (pHBE) cells, in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Airway epithelial cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD). Type 1 pro-inflammatory cytokines significantly increased the frequency of SPREADs, which coincided with epithelial barrier breakdown in differentiated pHBE cells. Furthermore, SPREADs correlated with IL-6 peptide secretion and the appearance of localized clusters of phospho-STAT3 immunofluorescence. To probe the mechanism of SPREADs, cells were co-treated with pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) or metabolic modulators (insulin, 2-deoxyglucose). Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence, implying that pro-inflammatory cytokines and glucose metabolism modulate SPREADs in human airway epithelial cells via secreted EGFR and IL6R ligands. We conclude that spatiotemporal ERK signaling plays a role in barrier homeostasis and dysfunction during inflammation of the airway epithelium. This novel signaling mechanism could be exploited clinically to supplement corticosteroid treatment for asthma and COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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