Abnormal Trafficking and Degradation of TLR4 Underlie the Elevated Inflammatory Response in Cystic Fibrosis

Abstract

Morbidity and mortality in cystic fibrosis (CF) are due not only to abnormal epithelial cell function, but also to an abnormal immune response. We have shown previously that macrophages lacking CFTR, the gene mutated in CF, contribute significantly to the hyper-inflammatory response observed in CF. Here we show for the first time that lack of functional CFTR in murine macrophages causes abnormal Toll like receptor (TLR) 4 subcellular localization. Upon LPS stimulation, CFTR macrophages have prolonged TLR4 retention in the early endosome and reduced translocation into the lysosomal compartment. This abnormal TLR4 trafficking leads to increased LPS-induced activation of the NF-kB, MAPK and IRF-3 pathways, and to decreased TLR4 degradation, which affects downregulation of the proinflammatory state. In addition to primary murine cells, mononuclear cells isolated from CF patients demonstrate similar defects in response to LPS. Moreover, specific inhibition of CFTR function induces abnormal TLR4 trafficking and enhances the inflammatory response of wildtype murine cells to LPS. Thus, functional CFTR in macrophages influences the physiological TLR4 spatial and temporal localization and perturbs LPS-mediated signaling in both murine CF models and patients with CF.

Regulatory role of β-arrestin-2 in cholesterol processing in cystic fibrosis epithelial cells

“…As mentioned above, we have demonstrated that ␤ 2-AR colocalizes with cholesterol in the perinuclear region ( 12 ). Recently Bruscia et al have shown in CF macrophages that toll-like receptor-4 (TLR4) accumulates in endosomes, leading to increased cytokine production ( 28 ). Further evidence of altered organelle movement can be seen in a study by Luciani et al showing that defective CFTR leads to decreased aggresome clearance and defective autophagy ( 29 ).…”

Ivacaftor-Induced Proteomic Changes Suggest Monocyte Defects May Contribute to the Pathogenesis of Cystic Fibrosis

“…Although most research on cystic fibrosis (CF) disease pathogenesis has focused on epithelia (1), recent work shows that CF transmembrane conductance regulator (CFTR) is expressed on human and murine monocytes and macrophages (2,3) and that CFTR deficiency could alter these cells' functions (2,4,5). Although these findings raise the possibility that immune dysfunction contributes to CF disease pathogenesis, questions remain.…”

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

“…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.…”

“…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).…”