Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, China.
Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, China.
Cell Death Dis. 2024 Jun 7;15(6):400. doi: 10.1038/s41419-024-06777-5.
Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1β, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1β were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1β was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1β production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.
越来越多的证据表明，细胞焦亡与哮喘的发病机制有关。Gasdermin D (GSDMD) 是细胞焦亡的执行者。GSDMD 在哮喘中的作用机制尚不清楚。本研究旨在阐明 GSDMD 在哮喘气道炎症和重塑中的潜在作用。通过免疫荧光染色评估哮喘患者和健康对照 (HC) 气道上皮组织中 N-GSDMD 的表达水平。ELISA 检测哮喘患者和健康个体血清样本中细胞因子 (IL-1β、IL-18、IL-17A 和 IL-10) 的浓度。结果表明，与对照组相比，轻度哮喘患者的 N-GSDMD、IL-18 和 IL-1β 水平显著升高。然后，使用野生型和 Gsdmd 敲除 (Gsdmd) 小鼠建立哮喘模型。通过组织病理学染色、ELISA 和流式细胞术，在体内研究 GSDMD 在过敏性气道炎症和组织重塑中的作用。结果发现，OVA 诱导的哮喘小鼠模型中 N-GSDMD、IL-18 和 IL-1β 的表达增强。Gsdmd 敲除导致哮喘小鼠的 BALF 和肺组织中 IL-18 和 IL-1β 产生减少。此外，Gsdmd 敲除的小鼠气道炎症和重塑明显减轻，这可能与 Th17 炎症反应和巨噬细胞 M2 极化减少有关。进一步研究发现，GSDMD 敲除可能通过靶向 Notch 信号通路调节巨噬细胞黏附、迁移和巨噬细胞 M2 极化，改善哮喘气道炎症和重塑。这些发现表明 GSDMD 缺乏可显著减轻过敏性炎症和组织重塑。因此，GSDMD 可能成为治疗哮喘的潜在靶点。
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