小鼠模型中的磷酸化蛋白质组学分析揭示ERK信号是儿童过敏性鼻炎相关鼻黏膜炎症反应的关键调节因子

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中文摘要

儿童过敏性鼻炎（AR）是一种多因素疾病，由遗传易感性与环境暴露之间的相互作用引起。尽管蛋白质磷酸化被广泛认为是多种生理和病理状态下基因表达的关键调节因素，但其在儿童AR患者鼻黏膜中的整体改变及其对黏膜功能和炎症通路的后续影响仍未完全阐明。本研究旨在阐明儿童AR诱导的鼻黏膜功能障碍的分子机制。我们的分析揭示了3,861种蛋白质，涵盖总共15,491个磷酸化位点。具体而言，我们在AR组鼻黏膜中检测到584种蛋白质上的441个下调磷酸化位点和722种蛋白质上的531个上调磷酸化位点。我们的蛋白质组学发现提示，免疫激活和代谢调节的失调可能促进AR的病理生理过程。通过对所鉴定磷酸化位点的通路分析，我们发现细胞外信号调节激酶（ERK）信号成为一条重要通路；值得注意的是，ERK1/2磷酸化的上调被观察到是与AR相关的显著标志物。重要的是，靶向ERK抑制剂为调节AR背景下关键炎症反应信号通路提供了一种潜在治疗策略，尽管这一发现来源于临床前小鼠模型，在考虑任何临床转化之前，需要在人类儿童鼻黏膜组织中进行严格验证。总体而言，这些发现强调，阐明小鼠模型中AR诱导的鼻黏膜功能障碍的分子机制，可能为儿童过敏相关疾病的新型治疗靶点提供信息。总体而言，阐明这些机制对于开发旨在减轻过敏性鼻炎相关炎症的靶向干预措施具有重大意义。

英文摘要

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.