PDF(Pubmed)
Abstract：
Neutrophil cytosolic factor 1 (Ncf1) is a major genetic factor associated with autoimmune diseases and has been identified as a key player in autoimmune mediated inflammation. We addressed the role of Ncf1 in an antigen-induced pulmonary inflammation model, and found that the Ncf1m1j mutation, causing a deficient reactive oxygen species response, alleviated disease. The Ncf1m1j mutation was associated with a reduced inflammatory cell infiltration in airways, but had limited effect on mucus secretion, antibody production and lung fibrosis. The disease remission in the Ncf1 mutated mice was reversed when functional Ncf1 was transgenically expressed in alveolar macrophages, suggesting that the cellular inflammation was depended on functional Ncf1 in alveolar macrophages. By determining cytokine and chemokine profiles in lung and serum, we found that Ncf1 deficiency allowed an increased expression of Th1 cytokines, including TNF-α, IFN-γ and IL-12. Since also epithelial cytokines were found to be regulated by Ncf1, we tested the effect of Ncf1 in IL-33 and IL-25 induced lung inflammation models. Mice with the Ncf1m1j mutation showed less sensitivity to IL-33, but not IL-25, induced lung inflammation, in a macrophage independent manner. The mice with deficient Ncf1 showed a reduced eosinophil infiltration and group 2 innate lymphoid cell (ILC2) activation. The production of IFN-γ in CD4+ T cells was increased, whereas IL-5 and IL-13 in ILC2 were decreased. Importantly, anti-IFN-γ antibody treatment of Ncf1 deficient mice increased eosinophil infiltration and rescued ILC2 activation in the lung. We conclude that Ncf1 deficiency enhances Th1 response, deactivates ILC2, and protects against pulmonitis.
摘要：
中性粒细胞胞质因子1（Ncf1）是与自身免疫性疾病相关的主要遗传因素，已被确定为自身免疫介导的炎症的关键参与者。我们讨论了Ncf1在抗原诱导的肺部炎症模型中的作用，发现Ncf1m1j突变,导致缺乏的活性氧响应，缓解疾病。Ncf1m1j突变与气道炎症细胞浸润减少有关，但对粘液分泌的影响有限，抗体产生和肺纤维化。当功能性Ncf1在肺泡巨噬细胞中转基因表达时，Ncf1突变小鼠的疾病缓解被逆转，提示细胞炎症依赖于肺泡巨噬细胞的功能性Ncf1。通过测定肺和血清中的细胞因子和趋化因子谱,我们发现Ncf1缺乏允许Th1细胞因子表达增加，包括TNF-α,IFN-γ和IL-12。由于还发现上皮细胞因子受Ncf1调节,我们测试了Ncf1在IL-33和IL-25诱导的肺部炎症模型中的作用。具有Ncf1m1j突变的小鼠对IL-33的敏感性较低，但对IL-25的敏感性却没有，以巨噬细胞独立的方式。Ncf1缺陷小鼠显示嗜酸性粒细胞浸润减少，第2组先天淋巴细胞（ILC2）激活。CD4+T细胞中IFN-γ的产生增加,而IL-5和IL-13在ILC2中降低。重要的是,抗IFN-γ抗体治疗Ncf1缺陷小鼠增加了嗜酸性粒细胞浸润并挽救了肺中的ILC2活化。我们得出结论，Ncf1缺乏增强Th1反应，使ILC2失活，并防止肺病。
