Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Am J Physiol Lung Cell Mol Physiol. 2011 May;300(5):L679-90. doi: 10.1152/ajplung.00202.2010. Epub 2011 Feb 18.
Contrary to the T-helper (Th)-2 bias and eosinophil-dominated bronchial inflammation encountered in most asthmatic subjects, other patients may exhibit neutrophil-predominant asthma subphenotypes, along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma subphenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic vs. neutrophilic asthma types, we developed an ovalbumin (OVA)-based mouse model of neutrophil-dominated allergic pulmonary inflammation. Consequently, we probed for particular inflammatory signatures and checkpoints underlying the immune pathology in this new model, as well as in a conventional, eosinophil-dominated asthma model. Briefly, mice were OVA sensitized using either aluminum hydroxide (alum) or complete Freund's adjuvants, followed by OVA aerosol challenge. T-cell, granulocyte, and inflammatory mediator profiles were determined, along with alveolar macrophage genomewide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/ complete Freund's adjuvants adjuvant-based sensitization, followed by allergen challenge, elicited a pulmonary inflammation that was poorly controlled by dexamethasone, and in which Th-1 and Th-17 cells additionally participated. Analysis of the overall pulmonary and alveolar macrophage inflammatory mediator profiles revealed remarkable similarities between both models. Nevertheless, we observed pronounced differences in the IL-12/IFN-γ axis and its control by IL-18 and IL-18 binding protein, but also in macrophage arachidonic acid metabolism and expression of T-cell instructive ligands. These differential signatures, superimposed onto a generic inflammatory signature, denote distinctive inflammatory checkpoints potentially involved in orchestrating neutrophil-dominated asthma.
与大多数哮喘患者中遇到的辅助性 T 细胞（Th）-2 偏向和嗜酸性粒细胞主导的支气管炎症相反，其他患者可能表现出以中性粒细胞为主的哮喘亚型，同时伴有 Th1 和 Th17 细胞。然而，许多以中性粒细胞为主的哮喘亚型的病因仍然知之甚少，部分原因是缺乏适当的实验模型。为了更好地了解嗜酸性粒细胞与中性粒细胞为主的哮喘类型的不同免疫病理特征，我们开发了一种基于卵清蛋白（OVA）的小鼠模型，用于中性粒细胞为主的变应性肺炎症。因此，我们在这个新模型以及传统的嗜酸性粒细胞为主的哮喘模型中，探究了潜在的免疫病理学的特定炎症特征和检查点。简而言之，使用氢氧化铝（明矾）或完全弗氏佐剂对小鼠进行 OVA 致敏，然后用 OVA 气溶胶进行挑战。确定了 T 细胞、粒细胞和炎症介质的特征，以及肺泡巨噬细胞的全基因组转录组特征。与明矾引发的 Th2 占主导的表型相反，OVA/完全弗氏佐剂佐剂致敏，然后用变应原进行挑战，引发了一种对地塞米松控制不佳的肺部炎症，其中 Th1 和 Th17 细胞也参与其中。对整体肺部和肺泡巨噬细胞炎症介质特征的分析表明，两种模型之间存在显著相似之处。然而，我们观察到在 IL-12/IFN-γ 轴及其由 IL-18 和 IL-18 结合蛋白控制方面存在显著差异，同时在巨噬细胞花生四烯酸代谢和 T 细胞指导配体的表达方面也存在差异。这些差异特征叠加在通用炎症特征上，表明潜在地参与协调以中性粒细胞为主的哮喘的独特炎症检查点。
