Abstract
BackgroundCystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Infections of the respiratory tract are a hallmark in CF. The host immune responses in CF are not adequate to eradicate pathogens, such as P. aeruginosa. Dendritic cells (DC) are crucial in initiation and regulation of immune responses. Changes in DC function could contribute to abnormal immune responses on multiple levels. The role of DC in CF lung disease remains unknown.MethodsThis study investigated the expression of CFTR gene in bone marrow-derived DC. We compared the differentiation and maturation profile of DC from CF and wild type (WT) mice. We analyzed the gene expression levels in DC from naive CF and WT mice or following P. aeruginosa infection.ResultsCFTR is expressed in DC with lower level compared to lung tissue. DC from CF mice showed a delayed in the early phase of differentiation. Gene expression analysis in DC generated from naive CF and WT mice revealed decreased expression of Caveolin-1 (Cav1), a membrane lipid raft protein, in the CF DC compared to WT DC. Consistently, protein and activity levels of the sterol regulatory element binding protein (SREBP), a negative regulator of Cav1 expression, were increased in CF DC. Following exposure to P. aeruginosa, expression of 3β-hydroxysterol-Δ7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP, was less decreased in the CF DC compared to WT DC.ConclusionThese results suggest that CFTR dysfunction in DC affects factors involved in membrane structure and lipid-metabolism, which may contribute to the abnormal inflammatory and immune response characteristic of CF.
Highlights
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a member of the ATP-binding cassette (ABC) protein family that functions as a cAMP-dependent chloride channel [1,2,3,4]
CF is primarily thought to be a disease of abnormal salt and fluid transport caused by the defective chloride channel function of the CFTR protein, dominant additional features of defective CFTR include an exaggerated inflammatory response and susceptibility to microbial colonization in the lung, with P. aeruginosa [5,6,7]
Among the genes showing expression change comparing wild type (WT) and CF dendritic cells (DC) upon P. aeruginosa infection, were 3 -hydroxysterol- 7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are regulated by sterol regulatory element binding protein (SREBP) [33,34,35,36,37]
Summary
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a member of the ATP-binding cassette (ABC) protein family that functions as a cAMP-dependent chloride channel [1,2,3,4]. CF is primarily thought to be a disease of abnormal salt and fluid transport caused by the defective chloride channel function of the CFTR protein, dominant additional features of defective CFTR include an exaggerated inflammatory response and susceptibility to microbial colonization in the lung, with P. aeruginosa [5,6,7]. Overall in CF, host immune responses do not seem to be adequate to eradicate P. aeruginosa from the respiratory tract Attention in this regard has been primarily focused on the role of CFTR in epithelial cells [8,9,10]. The widespread distribution of CFTR expression in non-epithelial cells and cells of the immune system implies a variety of functions, including a possible regulatory role in the secretion of cytokines and antibodies by lymphocytes and regulation of lipopolysaccharide (LPS) and interferon- induced macrophage activation[15,16]. The role of DC in CF lung disease remains unknown
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