Accumulation of long-chain unsaturated fatty acids in the airway inflammatory microenvironment drives eosinophil etosis and corticosteroid resistance.
作者信息
Bai Yurong, Fang Pengda, Li Shasha, Xiao Zhenhao, Chen Wenyi, Li Wenlong, Wang Xinyue, Chen Jingyuan, Li Yue, Chen Junhai, Huang Weiqiang, Luo Xin, Ueki Shigeharu, Fang Deyu, Yang Qintai, Zhang Yana
机构信息
Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangdong, Guangzhou, 510630, Guangdong, China.
Department of Allergy, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
出版信息
Cell Commun Signal. 2025 May 7;23(1):217. doi: 10.1186/s12964-025-02217-9.
BACKGROUND
Eosinophilic inflammation is a feature of chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with eosinophilic CRSwNP (ENP) tend to be refractory and prone to recurrence. Although there is increasing evidence linking lipid metabolic irregularities to eosinophilia, the particular lipid responsible for promoting eosinophilic inflammation and the precise molecular mechanisms involved remain unclear.
METHODS
Lipidomic atlas and metabolic pathway enrichment were identified by liquid chromatography-tandem mass spectrometry and RNA sequencing, respectively. Eosinophil extracellular trap cell death (EETosis) was detected by immunofluorescence microscopy and transmission electron microscopy. Functional analyses were performed on purified eosinophils.
RESULTS
The unbiased lipidomic atlas identified a specific accumulation in long-chain fatty acids (LCFAs) in ENP. Consistently, RNA-seq analysis confirmed the enrichment in long-chain unsaturated fatty acid metabolism pathway in ENP. In this lipid-rich airway inflammatory environment, EETosis including ETotic eosinophils, EETs release and Charcot-Leyden crystals (CLCs) generation was enhanced in ENP, and associated with disease severity. Further, we found that both saturated and unsaturated LCFAs, such as arachidonic acid, are critical fuel sources to trigger eosinophil activation and filamentous DNA release, whereas only arachidonic acid could induce crystalline Galectin10 (CLCs). Mechanistically, arachidonic acid induces EETosis through a mechanism independent of reactive oxygen species but the IRE1α/XBP1s/PAD4 pathway. Both the long-acting dexamethasone and short-acting hydrocortisone, while facilitate eosinophil apoptosis, are ineffective to block arachidonic acid-induced EETosis.
CONCLUSIONS
Our findings demonstrate a previously unknown role of the LCFA arachidonic acid in mediating EETosis and glucocorticoid insensitivity to drive ENP progression, which may lead to novel insights regarding the treatment of patients with refractory eosinophilic inflammation.
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