PDF(Pubmed)
Abstract：
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.
摘要：
新的证据表明，焦亡与哮喘的发病机理有关。GasderminD（GSDMD）是发烧的execution子手。GSDMD在哮喘中的作用机制尚不清楚。这项研究的目的是阐明GSDMD在哮喘气道炎症和重塑中的潜在作用。对哮喘患者和健康对照（HC）的气道上皮组织进行免疫荧光染色，以评估N-GSDMD的表达水平。ELISA用于测量细胞因子(IL-1β，IL-18,IL-17A,和IL-10）在从哮喘患者和健康个体收集的血清样品中。我们证明了N-GSDMD，与对照组相比，轻度哮喘样本中的IL-18和IL-1β显着增加。然后，采用野生型和Gsdmd基因敲除(Gsdmd-/-)小鼠建立哮喘模型。我们做了组织病理学染色,ELISA,和流式细胞术探讨GSDMD在变应性气道炎症和体内组织重塑中的作用。我们观察到N-GSDMD的表达，在OVA诱导的哮喘小鼠模型中IL-18和IL-1β增强。Gsdmd敲除导致哮喘小鼠支气管肺泡灌洗液（BALF）和肺组织中IL-18和IL-1β的产生减弱。此外,Gsdmd-/-小鼠表现出气道炎症和重塑的显著减少，这可能与巨噬细胞Th17炎症反应和M2极化减少有关。Further,我们发现GSDMD基因敲除可能通过调节巨噬细胞粘附改善哮喘气道炎症和重塑,迁移,和巨噬细胞M2极化通过靶向Notch信号通路。这些发现表明GSDMD缺乏可显著缓解过敏性炎症和组织重塑。因此,GSDMD可作为哮喘的潜在治疗靶点。
