多组学视角揭示全反式视黄酸在严重哮喘中对嗜酸性粒细胞的调控作用
2025/11/28
摘要
背景：严重哮喘的特征是持续的嗜酸性粒细胞炎症，但全反式视黄酸在嗜酸性粒细胞稳态中的作用尚不清楚。
目的：本研究探讨了ATRA在严重哮喘中嗜酸性粒细胞功能的调节作用。
方法：对来自健康参与者和严重哮喘患者的血液嗜酸性粒细胞进行了多组学分析（转录组学、蛋白质组学和脂质组学）。进一步通过流式细胞术和定量RT-PCR分析了ATRA对嗜酸性粒细胞功能的影响。
结果：对严重哮喘患者嗜酸性粒细胞的转录组学分析揭示了一个独特的基因表达特征，包括GGT5、IL2RA、CCL23和NOD2基因的上调，以及SPRY2和HIC1基因的下调。这种表型由2型细胞因子（IL-5和IL-4）和胞壁酰二肽驱动，但被ATRA反向调节。蛋白质组学分析显示，严重哮喘嗜酸性粒细胞中P-选择素糖蛋白配体-1的表达增加，该表达被2型细胞因子上调而被ATRA下调。脂质组学分析发现严重哮喘嗜酸性粒细胞中15-脂氧合酶代谢失调，ATRA选择性抑制半胱氨酰白三烯代谢，同时不影响15-脂氧合酶通路。对经ATRA处理的健康参与者嗜酸性粒细胞的多组学分析显示，IL1RL1和IL3RA特异性下调，降低了对IL-33和IL-3的反应性，从而将其与IL-5诱导的嗜酸性粒细胞区分开来。
结论：这些发现凸显了ATRA在维持嗜酸性粒细胞稳态和反向调节IL-5驱动的活化中的作用，从而为严重哮喘的潜在治疗策略提供了见解。
Multiomics insights into retinoic acid-mediated regulation of eosinophils in severe asthma
Miyata J, Sunata K, Sasaki H, et al.
Abstract
BACKGROUND:Severe asthma is marked by persistent eosinophilic inflammation, but the role of all-trans retinoic acid (ATRA) in eosinophil homeostasis remains unclear.
OBJECTIVE:This study examined the regulatory role of ATRA in eosinophil function in severe asthma.
METHODS:Multiomics analysis (transcriptomics, proteomics, and lipidomics) was conducted on blood eosinophils from healthy participants and patients with severe asthma. The effects of ATRA on eosinophil function were further analyzed by using flow cytometry and quantitative RT-PCR.
RESULTS:Transcriptomic profiling of eosinophils from patients with severe asthma revealed a distinct gene expression signature, with upregulation of the genes GGT5, IL2RA, CCL23, and NOD2 and downregulation of SPRY2 and HIC1. This phenotype was driven by type 2 cytokines (IL-5 and IL-4) and muramyl dipeptide but was counterregulated by ATRA. Proteomic analysis showed increased expression of P-selectin glycoprotein ligand-1 in SA-EOS, which was upregulated by type 2 cytokines and downregulated by ATRA. Lipidomic analysis identified dysregulated 15-lipoxygenase metabolism in SA-EOS, with ATRA selectively inhibiting cysteinyl leukotriene metabolism while sparing the 15-lipoxygenase pathway. Multiomics analysis of eosinophils from ATRA-treated healthy participants revealed specific downregulation of IL1RL1 and IL3RA, reducing responsiveness to IL-33 and IL-3 and distinguishing them from IL-5-induced eosinophils.
CONCLUSION:These findings highlight the role of ATRA in maintaining eosinophil homeostasis and counterregulating IL-5-driven activation, thus offering insights into potential therapeutic strategies for severe asthma.
背景：严重哮喘的特征是持续的嗜酸性粒细胞炎症，但全反式视黄酸在嗜酸性粒细胞稳态中的作用尚不清楚。
目的：本研究探讨了ATRA在严重哮喘中嗜酸性粒细胞功能的调节作用。
方法：对来自健康参与者和严重哮喘患者的血液嗜酸性粒细胞进行了多组学分析（转录组学、蛋白质组学和脂质组学）。进一步通过流式细胞术和定量RT-PCR分析了ATRA对嗜酸性粒细胞功能的影响。
结果：对严重哮喘患者嗜酸性粒细胞的转录组学分析揭示了一个独特的基因表达特征，包括GGT5、IL2RA、CCL23和NOD2基因的上调，以及SPRY2和HIC1基因的下调。这种表型由2型细胞因子（IL-5和IL-4）和胞壁酰二肽驱动，但被ATRA反向调节。蛋白质组学分析显示，严重哮喘嗜酸性粒细胞中P-选择素糖蛋白配体-1的表达增加，该表达被2型细胞因子上调而被ATRA下调。脂质组学分析发现严重哮喘嗜酸性粒细胞中15-脂氧合酶代谢失调，ATRA选择性抑制半胱氨酰白三烯代谢，同时不影响15-脂氧合酶通路。对经ATRA处理的健康参与者嗜酸性粒细胞的多组学分析显示，IL1RL1和IL3RA特异性下调，降低了对IL-33和IL-3的反应性，从而将其与IL-5诱导的嗜酸性粒细胞区分开来。
结论：这些发现凸显了ATRA在维持嗜酸性粒细胞稳态和反向调节IL-5驱动的活化中的作用，从而为严重哮喘的潜在治疗策略提供了见解。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol. 2025 Nov 7:S0091-6749(25)01119-4.DOI: 10.1016/j.jaci.2025.10.029.）
Multiomics insights into retinoic acid-mediated regulation of eosinophils in severe asthma
Miyata J, Sunata K, Sasaki H, et al.
Abstract
BACKGROUND:Severe asthma is marked by persistent eosinophilic inflammation, but the role of all-trans retinoic acid (ATRA) in eosinophil homeostasis remains unclear.
OBJECTIVE:This study examined the regulatory role of ATRA in eosinophil function in severe asthma.
METHODS:Multiomics analysis (transcriptomics, proteomics, and lipidomics) was conducted on blood eosinophils from healthy participants and patients with severe asthma. The effects of ATRA on eosinophil function were further analyzed by using flow cytometry and quantitative RT-PCR.
RESULTS:Transcriptomic profiling of eosinophils from patients with severe asthma revealed a distinct gene expression signature, with upregulation of the genes GGT5, IL2RA, CCL23, and NOD2 and downregulation of SPRY2 and HIC1. This phenotype was driven by type 2 cytokines (IL-5 and IL-4) and muramyl dipeptide but was counterregulated by ATRA. Proteomic analysis showed increased expression of P-selectin glycoprotein ligand-1 in SA-EOS, which was upregulated by type 2 cytokines and downregulated by ATRA. Lipidomic analysis identified dysregulated 15-lipoxygenase metabolism in SA-EOS, with ATRA selectively inhibiting cysteinyl leukotriene metabolism while sparing the 15-lipoxygenase pathway. Multiomics analysis of eosinophils from ATRA-treated healthy participants revealed specific downregulation of IL1RL1 and IL3RA, reducing responsiveness to IL-33 and IL-3 and distinguishing them from IL-5-induced eosinophils.
CONCLUSION:These findings highlight the role of ATRA in maintaining eosinophil homeostasis and counterregulating IL-5-driven activation, thus offering insights into potential therapeutic strategies for severe asthma.
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