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.
Methods: 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.
Results: 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.
Conclusion: 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.