哮喘联盟

    摘要
    背景：重症哮喘常表现为中性粒细胞型表型，伴随Th17细胞应答紊乱，但调控Th17细胞介导病变的分子机制尚不明确。
    目的：本研究证实组蛋白去乙酰化酶10（HDAC10）是重症哮喘中调控Th17细胞分化的关键分子。
    结果：哮喘模型小鼠与哮喘患者的CD4⁺T细胞中HDAC10表达上调。CD4⁺T细胞特异性敲除 Hdac10基因可通过抑制Th17细胞分化、减少IL-17A分泌，减轻中性粒细胞性气道炎症。机制研究显示，在Th17细胞内，HDAC10可直接结合信号转导与转录激活因子3（STAT3），并对STAT3第631位赖氨酸（K631）进行去乙酰化修饰；该翻译后修饰是Il-17a基因转录及后续中性粒细胞性气道炎症发生的必要条件。重要的是，药物抑制HDAC10能够阻断 Th17细胞应答，缓解中性粒细胞性气道炎症。
    结论：综上，本研究阐明HDAC10在调控Th17细胞致病效应中尚未被报道的新功能，提示 HDAC10可作为重症哮喘极具潜力的治疗靶点。
HDAC10 promotes Th17 differentiation and IL-17A-driven neutrophilic airway inflammation in severe asthma.
Zhong Y, Huang T, Feng Z, Quan J, Zhao Z, Su G, Huang J, Xiong Z, Xiang Y, Lai X, Lv Y, Lin H, Duan J, Lai T
Abstract
BACKGROUND:Severe asthma frequently manifests as a neutrophilic phenotype associated with dysregulated Th17 cell response, yet the molecular mechanism regulating Th17 cell-driven pathology remain poorly defined.
OBJECTIVE:Here, we identified histone deacetylase (HDAC) 10 as a critical regulator of Th17 cell differentiation in severe asthma.
RESULTS:HDAC10 expression in CD4+ T cells was upregulated in asthmatic mice and patients with asthma. CD4+ T cell-specific deletion of Hdac10 attenuated neutrophilic airway inflammation by dampening Th17 cell differentiation and subsequent IL-17A secretion. Mechanistically, HDAC10 directly bound to signal transducer and activator of transcription 3 (STAT3) and deacetylated it at lysine 631 (K631) in Th17 cells, a post-translational modification essential for Il-17a transcription and subsequent neutrophilic airway inflammation. Importantly, pharmacological inhibition of HDAC10 abrogated Th17 cell response and neutrophilic airway inflammation.
CONCLUSION:Together, our findings reveal an unrecognized role for HDAC10 in governing Th17 cell pathogenicity, highlighting HDAC10 as a promising therapeutic target for severe asthma.