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

Xu, Yaqin; Krause, Anja; Limberis, Maria P.; Worgall, Tilla S.; Worgall, Stefan

doi:10.1165/rcmb.2012-0021oc

Cited by 27 publications

(26 citation statements)

References 56 publications

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“…Finally, ΔF508 CFTR has been shown to cause dysfunctional, proinflammatory defects in: monocytes and macrophages [9,[46][47][48]; invariant natural killer T (iNKT) cells [49]; neutrophils [8]; dendritic cells [50,51]; T helper type 2 lymphocytes [52]; and B lymphocytes [53]. Bioinformatics analysis of gene expression data from the NCBI Gene Expression Omnibus indicates that suppressive effects on antigen presentation is through repression of the MHC class I antigen presentation genes in CF epithelia [54].…”

Section: Biological Basis For Differential Disease Severity In the Cfmentioning

confidence: 99%

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD

Wang

Cebotaru

Lee

et al. 2016

Cell Physiol Biochem

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Background/Aims: Chronic lung infection in cystic fibrosis leads to an inflammatory response that persists because of the chronic presence of bacteria and ultimately leads to a catastrophic failure of lung function. Methods: We use a combination of biochemistry, cell and molecular biology to study the interaction of TRADD, a key adaptor molecule in TNFα signaling, with CFTR in the regulation of NFκB. Results: We show that Wt CFTR binds to and colocalizes with TRADD. TRADD is a key signaling intermediate connecting TNFα with activation of NFκB. By contrast, ΔF508 CFTR does not bind to TRADD. NF-κB activation is higher in CFBE expressing ΔF508 CFTR than in cells expressing Wt CFTR. However, this differential effect is abolished when TRADD levels are knocked down. Transfecting Wt CFTR into CFBE cells reduces NF-κB activity. However the reduction is abolished by the CFTR chloride transport inhibitor-172. Consistently, transfecting in the correctly trafficked CFTR conduction mutants G551D or S341A also fail to reduce NFκB activity. Thus CFTR must be functional if it is to regulate NF-κB activity. We also found that TNFα produced a greater increase in NF-κB activity in CFBE cells than in the same cell when Wt CFTR-corrected. Consistently, the effect is also abolished when TRADD is knocked down by shRNA. Thus, Wt CFTR control of TRADD modulates the physiological activation of NF-κB by TNFα. Based on studies with proteosomal and lysosomal inhibitors, the mechanism by which Wt CFTR, but not ΔF508 CFTR, suppresses TRADD is by lysosomal degradation. Conclusion: We have uncovered a novel mechanism whereby Wt CFTR regulates TNFα signaling by enhancing TRADD degradation. Thus by reducing the levels of TRADD, Wt CFTR suppresses downstream proinflammatory NFκB signaling. By contrast, suppression of NF-κB activation fails in CF cells expressing ΔF508 CFTR.

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Section: Biological Basis For Differential Disease Severity In the Cfmentioning

confidence: 99%

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD

Wang

Cebotaru

Lee

et al. 2016

Cell Physiol Biochem

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“…Low levels of S1P in BAL fluids detected in CFTR knockout mice partly affect dendritic cell recruitment, which plays a crucial role in chronic infections in CF (Xu et al, 2013). …”

Section: S1p/sphks/s1pl Signaling Axis In Respiratory and Lung Dismentioning

confidence: 99%

“…Augmenting cystic fibrotic BALF with S1P recovered the expression of major histocompatibility complex class II molecules (MHCII), CD 40, and CD 86 in both wild type lung and blood dendritic cells (Xu et al, 2013). This finding argues that S1P could restore the innate immune function in CF.…”

Section: S1p/sphks/s1pl Signaling Axis In Respiratory and Lung Dismentioning

confidence: 99%

Targeting sphingosine-1-phosphate signaling in lung diseases

Ebenezer

Natarajan

2016

Pharmacology & Therapeutics

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Sphingosine-1- phosphate (S1P), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phosphatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL). As a ligand for specific G-protein-coupled receptors, S1P1–5, which are differentially expressed in different cell types, S1P generates downstream signals that play crucial role in developmental and disease related pathologies. In addition to acting extracellularly on receptors located on the plasma membrane, S1P can also act intracellularly, independently of S1P1–5, affecting calcium homeostasis and cell proliferation. The SphKs /S1P /S1PL metabolic pathway is implicated in numerous human pathologies including respiratory disorders, thereby raising the possibility that manipulating intracellular S1P levels could offer therapeutic potential in ameliorating lung diseases. This review focuses on the prospects of targeting S1P signaling and S1P metabolizing enzymes using small molecule inhibitors, receptor agonists, and antagonists in the treatment of lung diseases.

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“…CFTR dysfunction causes abnormalities in sphingolipid metabolism [82,83], and a decreased level of sphingosine-1-phosphate (S1P) was observed in CF lung disease [84,85], a ubiquitous signalling mediator that directs a diverse array of biological processes [86]. S1P formed by phosphorylation of sphingosine catalysed by two sphingosine kinases (SPHK1 and SPHK2) is a well-known bioactive lipid mediator, playing important roles in many tissue repair processes, including bone regeneration and osseous tissue growth in vivo [87].…”

Section: Cftr Dysfunction In Bone Cellsmentioning

confidence: 99%

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Jacquot

Delion²,

Gangloff³

et al. 2015

Osteoporos Int

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Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

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

Cited by 27 publications

References 56 publications

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD

Targeting sphingosine-1-phosphate signaling in lung diseases

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

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