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
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.
Cell Commun Signal. 2025 May 7;23(1):217. doi: 10.1186/s12964-025-02217-9.
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.
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.
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.
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.
嗜酸性粒细胞炎症是伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP）的一个特征。嗜酸性粒细胞性CRSwNP（ENP）患者往往难治且易于复发。尽管越来越多的证据表明脂质代谢异常与嗜酸性粒细胞增多有关，但促进嗜酸性粒细胞炎症的特定脂质以及所涉及的精确分子机制仍不清楚。
分别通过液相色谱-串联质谱法和RNA测序确定脂质组图谱和代谢途径富集情况。通过免疫荧光显微镜和透射电子显微镜检测嗜酸性粒细胞胞外陷阱细胞死亡（EETosis）。对纯化的嗜酸性粒细胞进行功能分析。
无偏倚脂质组图谱显示ENP中长链脂肪酸（LCFAs）有特异性积累。同样，RNA-seq分析证实ENP中长链不饱和脂肪酸代谢途径富集。在这种富含脂质的气道炎症环境中，ENP中包括ETotic嗜酸性粒细胞、EETs释放和夏科-莱登晶体（CLCs）生成的EETosis增强，并与疾病严重程度相关。此外，我们发现饱和和不饱和LCFAs，如花生四烯酸，都是触发嗜酸性粒细胞活化和丝状DNA释放的关键燃料来源，而只有花生四烯酸能诱导结晶半乳糖凝集素10（CLCs）。从机制上讲，花生四烯酸通过一种独立于活性氧但依赖IRE1α/XBP1s/PAD4途径的机制诱导EETosis。长效地塞米松和短效氢化可的松虽然都能促进嗜酸性粒细胞凋亡，但对阻断花生四烯酸诱导的EETosis无效。
我们的研究结果表明，长链脂肪酸花生四烯酸在介导EETosis和糖皮质激素不敏感性以推动ENP进展方面具有此前未知的作用，这可能为治疗难治性嗜酸性粒细胞炎症患者带来新的见解。
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