阻断迷走神经TRPA1-肺神经内分泌细胞信号通路可缓解哮喘严重程度
2025/08/18
摘要
背景：肺神经内分泌细胞（PNECs）毗邻支配肺部的迷走神经，且与哮喘发病机制有关，然而迷走神经-PNEC信号在哮喘中的神经免疫调节作用尚不明确。
方法：作者建立了C纤维光激活联合迷走神经切断术 (vagotomy) 的哮喘模型，观察PNECs的变化。对经流式细胞术分选的PNECs进行RNA测序，探究迷走神经C纤维对PNEC功能的影响，并通过体外细胞模型进一步验证。对支气管热成形术 (BT) 治疗前后患者的气道样本进行单细胞核RNA测序 (snRNA-seq)，深入分析BT治疗后不同气道细胞类型中神经信号的变化及其与PNEC的互作机制。
结果：迷走神经切断术可减少光激活TRPA1介导的PNEC活化及过敏性炎症，降低其数量与功能，从而减轻PNEC驱动的哮喘病理进程。PNEC RNA-seq结果显示，光激活肺部TRPA1可促进PNEC的迁移、聚集和突触传递，并增加神经肽的合成与分泌；此过程亦可由PNECs的α7 nAChR激活。支气管热成形术 (BT) 疗法通过干扰PNEC的分泌、突触形成及信号传导，显著减少或阻断PNEC与其他细胞间的NRG1-ERBB信号，从而缓解哮喘患者的病情。
结论：本研究发现迷走神经TRPA1-PNEC信号轴是驱动哮喘发生发展的关键因素。支气管热成形术可通过干扰PNEC与其他细胞间的NRG1-ERBB信号传导，从而缓解哮喘气道炎症。
关键词：NRG1-ERBB；肺神经内分泌细胞 (PNEC)；TRPA1；α7烟碱型乙酰胆碱受体 (α7 nAChR)；哮喘；支气管热成形术；迷走神经。
背景：肺神经内分泌细胞（PNECs）毗邻支配肺部的迷走神经，且与哮喘发病机制有关，然而迷走神经-PNEC信号在哮喘中的神经免疫调节作用尚不明确。
方法：作者建立了C纤维光激活联合迷走神经切断术 (vagotomy) 的哮喘模型，观察PNECs的变化。对经流式细胞术分选的PNECs进行RNA测序，探究迷走神经C纤维对PNEC功能的影响，并通过体外细胞模型进一步验证。对支气管热成形术 (BT) 治疗前后患者的气道样本进行单细胞核RNA测序 (snRNA-seq)，深入分析BT治疗后不同气道细胞类型中神经信号的变化及其与PNEC的互作机制。
结果：迷走神经切断术可减少光激活TRPA1介导的PNEC活化及过敏性炎症，降低其数量与功能，从而减轻PNEC驱动的哮喘病理进程。PNEC RNA-seq结果显示，光激活肺部TRPA1可促进PNEC的迁移、聚集和突触传递，并增加神经肽的合成与分泌；此过程亦可由PNECs的α7 nAChR激活。支气管热成形术 (BT) 疗法通过干扰PNEC的分泌、突触形成及信号传导，显著减少或阻断PNEC与其他细胞间的NRG1-ERBB信号，从而缓解哮喘患者的病情。
结论：本研究发现迷走神经TRPA1-PNEC信号轴是驱动哮喘发生发展的关键因素。支气管热成形术可通过干扰PNEC与其他细胞间的NRG1-ERBB信号传导，从而缓解哮喘气道炎症。
关键词：NRG1-ERBB；肺神经内分泌细胞 (PNEC)；TRPA1；α7烟碱型乙酰胆碱受体 (α7 nAChR)；哮喘；支气管热成形术；迷走神经。
（南方医科大学南方医院 樊可可 朱邦 赵文驱 赵海金）
（Feng X, Xue Y, et, al.Disruption of the Vagal TRPA1-Pulmonary Neuroendocrine Cell Axis Reduces Asthma Severity. Allergy. 2025 Jun 10. doi: 10.1111/all.16599. Epub ahead of print. PMID: 40491289.）
Abstract
Background: Pulmonary neuroendocrine cells (PNECs) are adjacent to the vagus nerve, which innervates the lungs, and have been implicated in asthma pathogenesis. However, the neuroimmunomodulatory role of vagal-PNEC signaling in asthma remains poorly understood.
Methods: We developed an asthma model of C-fiber photoactivation and vagotomy to investigate the changes in PNECs. RNA sequencing (RNA-seq) was performed on flow cytometry-sorted PNECs to explore how vagus nerve C fibers affect the function of PNECs, with further validation in an in vitro cell model. Single-nucleus RNA sequencing (snRNA-seq) was conducted on airway samples of patients before and after bronchial thermoplasty (BT) treatment, and the changes of neural signals in different airway cell types and their crosstalk with PNEC after BT were analyzed in depth.
Results: Vagotomy reduced photoactivated TRPA1-mediated PNEC activation and allergic inflammation, inhibited the number and function of PNEC, and attenuated PNEC-mediated asthma response. PNEC RNA-seq results showed that photoactivation of TRPA1 in lung could promote the migration, aggregation, and synaptic transmission of PNECs and increase the synthesis and secretion of neuropeptides, which could also be activated by α7 nAChR of PNECs. BT therapy significantly reduced or interrupted NRG1-ERBB signaling between PNECs and other cells by interfering with PNEC secretion, synapse formation, and signaling, thereby alleviating the condition of asthma patients.
Conclusions: We found that the vagal TRPA1-PNEC axis contributes to asthma severity. BT can disrupt this pathway through NRG1-ERBB signaling between PNECs and other cells to attenuate the inflammatory response in asthma.
Keywords: NRG1‐ERBB; PNEC; TRPA1; α7 nAChR; asthma; bronchial thermoplasty; vagus nerve.
Background: Pulmonary neuroendocrine cells (PNECs) are adjacent to the vagus nerve, which innervates the lungs, and have been implicated in asthma pathogenesis. However, the neuroimmunomodulatory role of vagal-PNEC signaling in asthma remains poorly understood.
Methods: We developed an asthma model of C-fiber photoactivation and vagotomy to investigate the changes in PNECs. RNA sequencing (RNA-seq) was performed on flow cytometry-sorted PNECs to explore how vagus nerve C fibers affect the function of PNECs, with further validation in an in vitro cell model. Single-nucleus RNA sequencing (snRNA-seq) was conducted on airway samples of patients before and after bronchial thermoplasty (BT) treatment, and the changes of neural signals in different airway cell types and their crosstalk with PNEC after BT were analyzed in depth.
Results: Vagotomy reduced photoactivated TRPA1-mediated PNEC activation and allergic inflammation, inhibited the number and function of PNEC, and attenuated PNEC-mediated asthma response. PNEC RNA-seq results showed that photoactivation of TRPA1 in lung could promote the migration, aggregation, and synaptic transmission of PNECs and increase the synthesis and secretion of neuropeptides, which could also be activated by α7 nAChR of PNECs. BT therapy significantly reduced or interrupted NRG1-ERBB signaling between PNECs and other cells by interfering with PNEC secretion, synapse formation, and signaling, thereby alleviating the condition of asthma patients.
Conclusions: We found that the vagal TRPA1-PNEC axis contributes to asthma severity. BT can disrupt this pathway through NRG1-ERBB signaling between PNECs and other cells to attenuate the inflammatory response in asthma.
Keywords: NRG1‐ERBB; PNEC; TRPA1; α7 nAChR; asthma; bronchial thermoplasty; vagus nerve.
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