IL-13/ATF4/S100P轴调控气道上皮屏障：嗜酸性粒细胞哮喘的新靶点
2026/07/31
摘要
背景：在过敏性哮喘中，主要由2型炎症驱动的气道上皮屏障破坏会形成恶性循环，使过敏原暴露于深层组织。然而，这一过程背后的具体机制仍不明确。
方法：研究人员利用公开数据集和独立的哮喘患者队列进行了生物信息学分析，并通过单细胞分析进一步阐明了S100钙结合蛋白P（S100P）在该疾病中的作用。为研究S100P对上皮屏障完整性的影响，采用白细胞介素-13（IL-13）刺激人支气管上皮细胞（16HBE）。同时，通过分子对接和分子动力学模拟评估了S100P与潜在治疗化合物之间的相互作用。
结果：研究发现，S100P的转录调控发生了显著改变，其蛋白水平与肺功能及嗜酸性粒细胞炎症程度密切相关。S100P主要定位于气道上皮细胞（AECs），尤其是在杯状细胞和Club细胞中表达丰富。S100P通过调控紧密连接蛋白（如ZO-1和Occludin）的表达以及改变跨上皮电阻，在维持上皮屏障完整性方面发挥关键作用。机制研究表明，IL-13可显著上调气道上皮细胞中的S100P表达，这一过程可能是通过激活转录因子4（ATF4）实现的。分子对接和分子动力学模拟显示，S100P能够与临床已应用的抗组胺药阿司咪唑（Astemizole）以及免疫抑制剂雷公藤红素（Celastrol）发生相互作用。这两种药物均能够减轻S100P介导的上皮屏障损伤。
结论：本研究确定了S100P是哮喘气道上皮屏障功能障碍的重要介导因子，并揭示了IL-13/ATF4/S100P信号轴在该过程中的关键作用。研究结果表明，S100P兼具生物标志物和治疗靶点的双重潜力，可为临床哮喘管理中的上皮屏障保护策略提供新的研究方向。
关键词：ATF4；哮喘；嗜酸性粒细胞；上皮屏障；S100P。
Abstract
Background: In allergic asthma, a detrimental cycle of epithelial barrier destruction, driven predominantly by type 2 inflammation, facilitates allergen exposure to deeper tissues. However, the precise mechanisms underlying this process remain poorly understood.
Methods: A bioinformatics analysis was performed using public datasets and an independent cohort of asthma patients. Single-cell profiling further elucidated the role of S100 calcium-binding protein P (S100P) in this condition. To investigate the impact of S100P on barrier integrity, human bronchial epithelial cells (16HBE) were stimulated with interleukin-13 (IL-13). The functional interaction between S100P and potential therapeutic compounds was evaluated by molecular docking and dynamics simulation.
Results: Our findings revealed significant alterations in the transcriptional regulation of the S100P, with protein levels correlating closely with lung function and eosinophilic inflammation. S100P was predominantly localized in airway epithelial cells (AECs), particularly in the goblet and club cells. It acts as a pivotal signal in maintaining epithelial barrier integrity by regulating tight junction proteins, such as ZO-1 and occludin, and altering transepithelial electrical resistance. Mechanistically, IL-13 markedly upregulated S100P expression in AECs, likely via activation of transcription factor 4 (ATF4). Molecular docking and dynamics simulations demonstrated that S100P interacts with the clinically established antihistamine astemizole and the immunosuppressant celastrol, both of which protect against S100P-induced barrier disruption.
Conclusions: Our work identified S100P as a key mediator of airway epithelial barrier dysfunction in asthma, shedding light on the crucial signaling of the IL-13/ATF4/S100P axis. These findings highlight the dual potential of S100P as both a biomarker and a therapeutic target, offering promising strategies for barrier protection in clinical asthma management.
Keywords: ATF4; Asthma; Eosinophil; Epithelial barrier; S100P.
背景：在过敏性哮喘中，主要由2型炎症驱动的气道上皮屏障破坏会形成恶性循环，使过敏原暴露于深层组织。然而，这一过程背后的具体机制仍不明确。
方法：研究人员利用公开数据集和独立的哮喘患者队列进行了生物信息学分析，并通过单细胞分析进一步阐明了S100钙结合蛋白P（S100P）在该疾病中的作用。为研究S100P对上皮屏障完整性的影响，采用白细胞介素-13（IL-13）刺激人支气管上皮细胞（16HBE）。同时，通过分子对接和分子动力学模拟评估了S100P与潜在治疗化合物之间的相互作用。
结果：研究发现，S100P的转录调控发生了显著改变，其蛋白水平与肺功能及嗜酸性粒细胞炎症程度密切相关。S100P主要定位于气道上皮细胞（AECs），尤其是在杯状细胞和Club细胞中表达丰富。S100P通过调控紧密连接蛋白（如ZO-1和Occludin）的表达以及改变跨上皮电阻，在维持上皮屏障完整性方面发挥关键作用。机制研究表明，IL-13可显著上调气道上皮细胞中的S100P表达，这一过程可能是通过激活转录因子4（ATF4）实现的。分子对接和分子动力学模拟显示，S100P能够与临床已应用的抗组胺药阿司咪唑（Astemizole）以及免疫抑制剂雷公藤红素（Celastrol）发生相互作用。这两种药物均能够减轻S100P介导的上皮屏障损伤。
结论：本研究确定了S100P是哮喘气道上皮屏障功能障碍的重要介导因子，并揭示了IL-13/ATF4/S100P信号轴在该过程中的关键作用。研究结果表明，S100P兼具生物标志物和治疗靶点的双重潜力，可为临床哮喘管理中的上皮屏障保护策略提供新的研究方向。
关键词：ATF4；哮喘；嗜酸性粒细胞；上皮屏障；S100P。
（南方医科大学南方医院 凌嘉骏 赵海金）
（Li D, Yin Y, Hao R, Ren Y, Gu S, Wang H, Han L, Ye S, Li L, Yao X, Zeng X. S100P mediates IL-13/ATF4-driven epithelial barrier dysfunction in eosinophilic asthma: a potential biomarker and therapeutic target. J Transl Med. 2026 Apr 24;24(1):755. doi: 10.1186/s12967-026-08132-y. PMID: 42032605; PMCID: PMC13255357.）Abstract
Background: In allergic asthma, a detrimental cycle of epithelial barrier destruction, driven predominantly by type 2 inflammation, facilitates allergen exposure to deeper tissues. However, the precise mechanisms underlying this process remain poorly understood.
Methods: A bioinformatics analysis was performed using public datasets and an independent cohort of asthma patients. Single-cell profiling further elucidated the role of S100 calcium-binding protein P (S100P) in this condition. To investigate the impact of S100P on barrier integrity, human bronchial epithelial cells (16HBE) were stimulated with interleukin-13 (IL-13). The functional interaction between S100P and potential therapeutic compounds was evaluated by molecular docking and dynamics simulation.
Results: Our findings revealed significant alterations in the transcriptional regulation of the S100P, with protein levels correlating closely with lung function and eosinophilic inflammation. S100P was predominantly localized in airway epithelial cells (AECs), particularly in the goblet and club cells. It acts as a pivotal signal in maintaining epithelial barrier integrity by regulating tight junction proteins, such as ZO-1 and occludin, and altering transepithelial electrical resistance. Mechanistically, IL-13 markedly upregulated S100P expression in AECs, likely via activation of transcription factor 4 (ATF4). Molecular docking and dynamics simulations demonstrated that S100P interacts with the clinically established antihistamine astemizole and the immunosuppressant celastrol, both of which protect against S100P-induced barrier disruption.
Conclusions: Our work identified S100P as a key mediator of airway epithelial barrier dysfunction in asthma, shedding light on the crucial signaling of the IL-13/ATF4/S100P axis. These findings highlight the dual potential of S100P as both a biomarker and a therapeutic target, offering promising strategies for barrier protection in clinical asthma management.
Keywords: ATF4; Asthma; Eosinophil; Epithelial barrier; S100P.
