Macrophages Directly Contribute to the Exaggerated Inflammatory Response in Cystic Fibrosis Transmembrane Conductance Regulator^−/− Mice

Abstract

Pulmonary infection with an exaggerated inflammatory response is the major cause of morbidity and mortality in cystic fibrosis (CF). The objective of this study was to determine whether differences in the innate immune system underlie the exaggerated immune response in CF. We established a model that recapitulates the exaggerated immune response in a CF mouse model by exposure to Pseudomonas aeruginosa LPS and assessed the pulmonary cellular and cytokine responses of wild-type (WT) and CF mice. Compared with WT mice, CF mice had increased numbers of neutrophils and increased proinflammatory cytokines in their bronchoalveolar lavage fluid after LPS exposure. Based on the increased levels of IL-1a, IL-6, granulocyte colony-stimulating factor (G-CSF), and keratinocyte chemoattractant, all of which are known to be produced by macrophages, we tested whether two populations of macrophages, bone marrowderived macrophages and alveolar macrophages, directly contribute to the elevated cytokine response of CF mice to LPS. After in vitro stimulation of bone marrow-derived macrophages and alveolar macrophages with LPS, IL-1a, IL-6, G-CSF, and monocyte chemoattractant protein-1 were higher in CF compared with WT cell supernatants. Quantitative analyses for IL-6 and keratinocyte chemoattractant revealed that LPS-stimulated CF macrophages have higher mRNA and intracellular protein levels compared with WT macrophages. Our data support the hypothesis that macrophages play a role in the exuberant cytokine production and secretion that characterizes CF, suggesting that the macrophage response may be an important therapeutic target for decreasing the morbidity of CF lung disease.

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

“…The dysregulated cytokine secretion of CF epithelial cells plays an important role in creating the inflammatory milieu (3). It has become increasingly clear that the cystic fibrosis transmembrane regulator (CFTR) also plays a role in lung immune cells, and that the dysfunction of the CFTR affects immune cell responses (4)(5)(6)(7)(8)(9)(10)(11). The dysfunction of pulmonary immune cells in CF could result from the lack of their own CFTR function, or may be induced by the altered milieu created by defective CFTR function in epithelial cells (5,8).…”

“…The dysfunction or lack of CFTR expression in macrophages, neutrophils, and dendritic cells (DCs) results in an inflammatory phenotype (4,5,(8)(9)(10)(11). In addition, antigen presentation is affected in CF.…”

Alveolar macrophages and CC chemokines are increased in children with cystic fibrosis

“…HUBEAU et al [10] reported an increased presence of alveolar macrophages in the lungs of late gestational fetuses with CF compared with non-CF fetuses. In addition, BRUSCIA et al [11] reported that macrophages from CF transmembrane conductance regulator (CFTR) knockout mice show exaggerated inflammatory cytokine responses to bacterial lipopolysaccharide; in some cases these increases were dose dependent with intermediate changes present in heterozygotes. These data suggest that dysregulation of macrophage recruitment and/or function may be intrinsic to CF prior to the development of pulmonary infection and may be driven in some manner by CFTR dysfunction.…”

Immune Dysfunction in Cystic Fibrosis

“…Although it is still debated if inflammation precedes infection in the lungs of infants and young children with CF, it is undisputed that CFTR is linked to the NFB pathway, a crucial transcription activator for inflammatory and immune responses. These intrinsic activations of NFB and cytokines, such as IL-8 and tumor necrosis factor alpha (TNF-), have been observed both in naïve lung macrophages from CFTR knockout mice (CF mice) and in un-stimulated human macrophages with decreased CFTR expression (Bruscia EM 2008, Xu Y 2010. It seems that the intrinsic activation of NFB-mediated inflammatory cytokine release is independent of the chloride channel function of the CFTR protein.…”