Redox-dependent suppression of ATF3 impairs steroid sensitivity in asthma through MKP-1/p38 MAPK signaling

作者：Jinxiu Li, Lei Zhao, Yali Qiu, Jiawei Liao, Xue Tian, Jianwei Gao, Min Zhang, Aihua Bao · 发表于：Free Radical Biology and Medicine · 年份：2025 · DOI：10.1016/j.freeradbiomed.2025.11.011 · 被引用次数：2 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Redox biology and oxidative stress、Medical and Biological Ozone Research

Chronic oxidative stress (OS) is a critical contributor to steroid insensitivity (SI) in asthma, in which p38 mitogen-activated protein kinase (p38 MAPK) overactivation playing a central role. Although mitogen-activated protein kinase phosphatase-1 (MKP-1) downregulation has been implicated in this process, the redox-sensitive upstream regulators remain poorly understood. This study aimed to elucidate the role of activating transcription factor 3 (ATF3) in chronic OS-induced SI using an ovalbumin-ozone (OVA-ozone) murine asthma model. Chronic (8-week) ozone exposure led to sustained ROS accumulation and significantly reduced ATF3 and MKP-1 expression in lung tissue, contrasting with the upregulation observed under acute conditions. A steroid-insensitive asthma model was successfully established through chronic ozone exposure combined with repeated OVA stimulations, in which the inhibitory effects of Dexamethasone (DEX) on the pulmonary inflammation and lung function were substantially blunted. Treatment with antioxidant or gene augmentation of ATF3 can both restored the steroids insensitivity of this chronic OVA-ozone asthma model, accompanied by elevated ATF3 and MKP-1 expression and suppressed p38 MAPK phosphorylation. Furthermore, steroid sensitivity of allergic asthma model established with ATF3 knockout mice was blunted, while genetic supplementation of ATF3 gene can partly restore the inhibitory effects of DEX. Particularly, in vitro, ATF3 gene was shown to transactivat...