Human Pulmonary Neuroendocrine Cells Respond to House Dust Mite Extract With PAR-1 Dependent Release of CGRP.

IF 12.6 1区 医学 Q1 ALLERGY Allergy Pub Date : 2024-11-27 DOI:10.1111/all.16416
Ritu Mann-Nüttel, Shivani Mandal, Marie Armbruster, Lakshmi Puttagunta, Paul Forsythe
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Abstract

Background: Pulmonary neuroendocrine cells (PNEC) are rare airway epithelial cells that have recently gained attention as potential amplifiers of allergic asthma. However, studying PNEC function in humans has been challenging due to a lack of cell isolation methods, and little is known about human PNEC function in response to asthma-relevant stimuli. Here we developed and characterized an in vitro human PNEC model and investigated the neuroendocrine response to extracts of the common aeroallergen house dust mite (HDM).

Methods: PNEC-enriched cultures were generated from human induced pluripotent stem cells (iPNEC) and primary bronchial epithelial cells (ePNEC). Characterized PNEC cultures were exposed to HDM extract, a volatile chemical odorant (Bergamot oil), or the bacterial membrane component, lipopolysaccharide (LPS), and neuroendocrine gene expression and neuropeptide release determined.

Results: Both iPNEC and ePNEC models demonstrated similar baseline neuroendocrine characteristics and a stimuli-specific modulation of gene expression. Most notably, exposure to HDM but not Bergamot oil or LPS, leads to dose-dependent induction of the CGRP encoding gene, CALCB, and corresponding release of the neuropeptide. HDM-induced CALCB expression and CGRP release could be inhibited by a protease-activated receptor 1 (PAR1) antagonist or protease inhibitors and was mimicked by a PAR1 agonist.

Conclusions: We have characterized a novel model of PNEC-enriched human airway epithelium and utilized this model to demonstrate a previously unrecognized role for human PNEC in mediating a direct neuroendocrine response to aeroallergen exposure.

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人类肺部神经内分泌细胞对屋尘螨提取物的反应与 PAR-1 依赖性 CGRP 的释放有关。
背景:肺神经内分泌细胞(PNEC)是一种罕见的气道上皮细胞,最近作为过敏性哮喘的潜在放大器而受到关注。然而,由于缺乏细胞分离方法,研究人类肺神经内分泌细胞的功能具有挑战性,而且人们对人类肺神经内分泌细胞在哮喘相关刺激下的功能知之甚少。在此,我们开发了一种体外人类 PNEC 模型并对其进行了表征,同时研究了神经内分泌对常见过敏原屋尘螨(HDM)提取物的反应:方法:从人类诱导多能干细胞(iPNEC)和原代支气管上皮细胞(ePNEC)中产生了PNEC富集培养物。表征后的 PNEC 培养物暴露于 HDM 提取物、挥发性化学气味剂(佛手柑油)或细菌膜成分脂多糖(LPS),并测定神经内分泌基因的表达和神经肽的释放:结果:iPNEC 和 ePNEC 模型都表现出相似的神经内分泌基线特征和基因表达的特异性刺激调节。最值得注意的是,暴露于 HDM 而不是佛手柑油或 LPS 会导致 CGRP 编码基因 CALCB 的剂量依赖性诱导和相应的神经肽释放。蛋白酶激活受体 1(PAR1)拮抗剂或蛋白酶抑制剂可抑制 HDM 诱导的 CALCB 表达和 CGRP 释放,PAR1 激动剂也可模拟 HDM 诱导的 CALCB 表达和 CGRP 释放:我们鉴定了一种新的富含 PNEC 的人类气道上皮细胞模型,并利用该模型证明了人类 PNEC 在介导神经内分泌对接触空气过敏原的直接反应方面发挥了以前未曾认识到的作用。
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来源期刊
Allergy
Allergy 医学-过敏
CiteScore
26.10
自引率
9.70%
发文量
393
审稿时长
2 months
期刊介绍: Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality. Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.
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