Zhang Huanping, Chen Xiaoxue, Liu Le, Zheng Haoyue, Yang Xing, Yin Kai, Yao Qi, Li Lei, Yang Pingchang
Department of Allergy Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen, People's Republic of China.
Int J Nanomedicine. 2025 Jul 14;20:9019-9030. doi: 10.2147/IJN.S535265. eCollection 2025.
Allergic airway inflammation, characterized by Th2 cytokine production and eosinophilic infiltration, is a hallmark of asthma. The airway epithelium plays a pivotal role in orchestrating allergic responses by releasing cytokines such as oncostatin M (OSM). This study investigates the role of OSM in dust mite extract (DME)-induced allergic airway inflammation and identifies a novel mechanism by which OSM drives Th2-polarized inflammation.
A murine model of DME-induced airway inflammation was established. Mice were treated with CelEd, a nanoparticle carrying fibroblast-targeting device and ATF4 siRNA.
We observed that DME exposure significantly upregulates OSM expression in airway epithelial cells, both at the mRNA and protein levels. This finding was corroborated in human bronchial epithelial cell lines, where DME exposure induced dose-dependent OSM secretion. Intranasal administration of OSM in naïve mice phenocopied the hallmark features of allergic inflammation, including eosinophilic infiltration and elevated Th2 cytokines, highlighting OSM's sufficiency to drive allergic responses. Mechanistically, we discovered that OSM promotes IL-4 production through fibroblast reprogramming, involving endoplasmic reticulum stress (ERS) activation. OSM signaling in fibroblasts led to ERS and subsequent activation of the PERK-eIF2α-ATF4 pathway, which drives IL-4 transcription via the ATF4/Mef2d/GATA3 axis. Importantly, targeting this pathway through fibroblast-specific ATF4 knockdown significantly alleviated allergic pathology, including airway eosinophilia, Th2 cytokine production, and airway hyperresponsiveness.
These findings underscore the critical role of OSM in allergic airway inflammation and identify the OSM-ERS-IL-4 axis as a potential therapeutic target for asthma and other allergic diseases.
以Th2细胞因子产生和嗜酸性粒细胞浸润为特征的过敏性气道炎症是哮喘的一个标志。气道上皮细胞通过释放诸如抑瘤素M（OSM）等细胞因子在协调过敏反应中起关键作用。本研究调查了OSM在尘螨提取物（DME）诱导的过敏性气道炎症中的作用，并确定了OSM驱动Th2极化炎症的一种新机制。
建立DME诱导的气道炎症小鼠模型。用CelEd处理小鼠，CelEd是一种携带成纤维细胞靶向装置和ATF4小干扰RNA的纳米颗粒。
我们观察到，暴露于DME后，气道上皮细胞中OSM的mRNA和蛋白水平均显著上调。在人支气管上皮细胞系中也证实了这一发现，其中暴露于DME会诱导剂量依赖性的OSM分泌。在未致敏小鼠中鼻内给予OSM可模拟过敏性炎症的标志性特征，包括嗜酸性粒细胞浸润和Th2细胞因子升高，突出了OSM驱动过敏反应的充分性。从机制上讲，我们发现OSM通过成纤维细胞重编程促进IL-4的产生，这涉及内质网应激（ERS）激活。成纤维细胞中的OSM信号导致ERS以及随后PERK-eIF2α-ATF4途径激活，该途径通过ATF4/Mef2d/GATA3轴驱动IL-4转录。重要的是，通过成纤维细胞特异性敲低ATF4靶向该途径可显著减轻过敏性病理，包括气道嗜酸性粒细胞增多、Th2细胞因子产生和气道高反应性。
这些发现强调了OSM在过敏性气道炎症中的关键作用，并确定OSM-ERS-IL-4轴为哮喘和其他过敏性疾病的潜在治疗靶点。
