调节性T细胞中p300依赖性调节在过敏性哮喘中起关键作用
2025/10/31
摘要
理由：哮喘是一种慢性炎症性气道疾病，受表观遗传修饰的影响。E1A结合蛋白p300（p300）是一种关键的组蛋白乙酰转移酶，可调节多种基因的转录。
目的：我们研究了p300在调节过敏性哮喘免疫反应中的作用。
方法：在具有全身性p300缺失和调节性T细胞（Treg）特异性p300缺失的小鼠中建立过敏原诱导的哮喘模型。在哮喘诱导的小鼠和哮喘患者的活检样品中评估组蛋白乙酰转移酶活性和p300表达。接下来，研究了T辅助细胞2和Tregs的免疫应答。另外，使用分选的Tregs进行染色质免疫沉淀和RNA测序。通过体外抑制和过表达试验证实了Tregs中鸟苷酸结合蛋白5（GBP5）的功能研究。
测量和主要结果：哮喘小鼠组蛋白乙酰转移酶活性和p300水平升高。哮喘患者的p300表达也高于对照组。具有系统性p300缺失的小鼠具有升高的2型免疫应答并降低Treg群体和功能。此外，p300缺失降低了Tregs的抑制能力和分化潜能。Treg特异性p300缺失的小鼠过敏性炎症也加剧。染色质免疫沉淀和RNA测序显示GBP5是Tregs中p300的主要靶基因。GBP5过表达改善了由p300消耗引起的Treg增殖的减少。
结论：p300通过增强Treg功能，部分通过GBP5介导的调节，从而抑制Th2驱动的气道炎症，在过敏性哮喘中发挥保护作用。
p300-Dependent Modulation in Regulatory T Cells Plays a Crucial Role in Allergic Asthma
Eun Gyul Kim, Mi Na Kim, Soo-Yeon Park, Chang Hyun Park, Joo Yeon Cho, Byung Chan Ko, Sung Woo Park, Kyung Won Kim, Ho-Geun Yoon, Myung Hyun Sohn
Abstract
Rationale: Asthma is a chronic inflammatory airway disease, affected by epigenetic modifications. E1A binding protein p300 (p300) is a pivotal histone acetyltransferase that regulates the transcription of diverse genes.
Objectives: We investigated the role of p300 in regulating immune responses during allergic asthma.
Methods: An allergen-induced asthma model was established in mice with systemic p300 deletion and regulatory T cell (Treg)-specific p300 deletion. Histone acetyltransferase activity and p300 expression were evaluated in asthma-induced mice and biopsy samples from patients with asthma. Next, immune responses of T helper 2 cells and Tregs were investigated. Additionally, chromatin immunoprecipitation- and RNA-sequencing were conducted using the sorted Tregs. Functional studies of guanylate binding protein 5 (GBP5) in Tregs were confirmed through in vitro inhibition and overexpression tests.
Measurements and main results: Histone acetyltransferase activity and p300 levels were elevated in mice with asthma. p300 expression was also higher in patients with asthma than in control subjects. Mice with systemic p300 deletion had elevated type-2 immune responses and decreased Treg population and functions. Furthermore, p300 deletion reduced the suppression ability and differentiation potential of Tregs. Allergic inflammation was also exacerbated in mice with Treg-specific p300 deletion. Chromatin immunoprecipitation- and RNA-sequencing revealed GBP5 as a primary target gene of p300 in Tregs. GBP5 overexpression ameliorated the reduction in Treg proliferation caused by p300 depletion.
Conclusions: p300 plays a protective role in allergic asthma by enhancing Treg function, partly through GBP5-mediated regulation, thereby suppressing Th2-driven airway inflammation.
理由：哮喘是一种慢性炎症性气道疾病，受表观遗传修饰的影响。E1A结合蛋白p300（p300）是一种关键的组蛋白乙酰转移酶，可调节多种基因的转录。
目的：我们研究了p300在调节过敏性哮喘免疫反应中的作用。
方法：在具有全身性p300缺失和调节性T细胞（Treg）特异性p300缺失的小鼠中建立过敏原诱导的哮喘模型。在哮喘诱导的小鼠和哮喘患者的活检样品中评估组蛋白乙酰转移酶活性和p300表达。接下来，研究了T辅助细胞2和Tregs的免疫应答。另外，使用分选的Tregs进行染色质免疫沉淀和RNA测序。通过体外抑制和过表达试验证实了Tregs中鸟苷酸结合蛋白5（GBP5）的功能研究。
测量和主要结果：哮喘小鼠组蛋白乙酰转移酶活性和p300水平升高。哮喘患者的p300表达也高于对照组。具有系统性p300缺失的小鼠具有升高的2型免疫应答并降低Treg群体和功能。此外，p300缺失降低了Tregs的抑制能力和分化潜能。Treg特异性p300缺失的小鼠过敏性炎症也加剧。染色质免疫沉淀和RNA测序显示GBP5是Tregs中p300的主要靶基因。GBP5过表达改善了由p300消耗引起的Treg增殖的减少。
结论：p300通过增强Treg功能，部分通过GBP5介导的调节，从而抑制Th2驱动的气道炎症，在过敏性哮喘中发挥保护作用。
（中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校）
（Am J Respir Crit Care Med. 2025 Oct 6. doi: 10.1164/rccm.202407-1410OC.）
p300-Dependent Modulation in Regulatory T Cells Plays a Crucial Role in Allergic Asthma
Eun Gyul Kim, Mi Na Kim, Soo-Yeon Park, Chang Hyun Park, Joo Yeon Cho, Byung Chan Ko, Sung Woo Park, Kyung Won Kim, Ho-Geun Yoon, Myung Hyun Sohn
Abstract
Rationale: Asthma is a chronic inflammatory airway disease, affected by epigenetic modifications. E1A binding protein p300 (p300) is a pivotal histone acetyltransferase that regulates the transcription of diverse genes.
Objectives: We investigated the role of p300 in regulating immune responses during allergic asthma.
Methods: An allergen-induced asthma model was established in mice with systemic p300 deletion and regulatory T cell (Treg)-specific p300 deletion. Histone acetyltransferase activity and p300 expression were evaluated in asthma-induced mice and biopsy samples from patients with asthma. Next, immune responses of T helper 2 cells and Tregs were investigated. Additionally, chromatin immunoprecipitation- and RNA-sequencing were conducted using the sorted Tregs. Functional studies of guanylate binding protein 5 (GBP5) in Tregs were confirmed through in vitro inhibition and overexpression tests.
Measurements and main results: Histone acetyltransferase activity and p300 levels were elevated in mice with asthma. p300 expression was also higher in patients with asthma than in control subjects. Mice with systemic p300 deletion had elevated type-2 immune responses and decreased Treg population and functions. Furthermore, p300 deletion reduced the suppression ability and differentiation potential of Tregs. Allergic inflammation was also exacerbated in mice with Treg-specific p300 deletion. Chromatin immunoprecipitation- and RNA-sequencing revealed GBP5 as a primary target gene of p300 in Tregs. GBP5 overexpression ameliorated the reduction in Treg proliferation caused by p300 depletion.
Conclusions: p300 plays a protective role in allergic asthma by enhancing Treg function, partly through GBP5-mediated regulation, thereby suppressing Th2-driven airway inflammation.
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农场灰尘提取物在嗜酸性粒细胞炎症小鼠模型中的治疗潜力
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Linarin 通过 ALDH2 调节保护哮喘诱导的气道上皮铁死亡和炎症
