Siegmann Nanna, Worbs David, Effinger Frauke, Bormann Tobias, Gebhardt Madlen, Ulrich Martina, Wermeling Fredrik, Müller-Hermelink Eva, Biedermann Tilo, Tighe Mike, Edwards Michael J, Caldwell Charles, Leadbetter Elizabeth, Karlsson Mikael C I, Becker Katrin Anne, Gulbins Erich, Döring Gerd
Institute of Medical Microbiology and Hygiene University Hospital, Tübingen, Germany.
Cell Physiol Biochem. 2014;34(1):56-70. doi: 10.1159/000362984. Epub 2014 Jun 16.
BACKGROUND/AIMS: Inflammation is a major and critical component of the lung pathology in the hereditary disease cystic fibrosis. The molecular mechanisms of chronic inflammation in cystic fibrosis require definition.
We used several genetic mouse models to test a role of iNKT cells and ceramide in pulmonary inflammation of cystic fibrosis mice. Inflammation was determined by the pulmonary cytokine profil and the abundance of inflammatory cells in the lung.
Here we provide a new concept how inflammation in the lung of individuals with cystic fibrosis is initiated. We show that in cystic fibrosis mice the mutation in the Cftr gene provokes a significant up-regulation of iNKT cells in the lung. Accumulation of iNKT cells serves to control autoimmune disease, which is triggered by a ceramide-mediated induction of cell death in CF organs. Autoimmunity becomes in particular overt in cystic fibrosis mice lacking iNKT cells and although suppression of the autoimmune response by iNKT cells is beneficial, IL-17(+) iNKT cells attract macrophages and neutrophils to CF lungs resulting in chronic inflammation. Genetic deletion of iNKT cells in cystic fibrosis mice prevents inflammation in CF lungs.
Our data demonstrate an important function of iNKT cells in the chronic inflammation affecting cystic fibrosis lungs. iNKT cells suppress the auto-immune response induced by ceramide-mediated death of epithelial cells in CF lungs, but also induce a chronic pulmonary inflammation.
背景/目的：炎症是遗传性疾病囊性纤维化肺部病理的主要且关键的组成部分。囊性纤维化慢性炎症的分子机制有待明确。
我们使用了几种基因小鼠模型来测试不变自然杀伤T细胞（iNKT细胞）和神经酰胺在囊性纤维化小鼠肺部炎症中的作用。通过肺部细胞因子谱和肺内炎症细胞的丰度来确定炎症情况。
在此我们提出了一个关于囊性纤维化患者肺部炎症如何起始的新概念。我们发现，在囊性纤维化小鼠中，Cftr基因的突变会引发肺部iNKT细胞显著上调。iNKT细胞的积累有助于控制自身免疫性疾病，该疾病由神经酰胺介导的CF器官细胞死亡诱导引发。在缺乏iNKT细胞的囊性纤维化小鼠中，自身免疫尤为明显，尽管iNKT细胞对自身免疫反应的抑制是有益的，但IL-17(+) iNKT细胞会吸引巨噬细胞和中性粒细胞至CF肺部，导致慢性炎症。在囊性纤维化小鼠中基因删除iNKT细胞可预防CF肺部的炎症。
我们的数据证明了iNKT细胞在影响囊性纤维化肺部的慢性炎症中具有重要作用。iNKT细胞抑制CF肺部由神经酰胺介导的上皮细胞死亡所诱导的自身免疫反应，但也会引发慢性肺部炎症。
