Rescue of dysfunctional autophagy attenuates hyperinflammatory responses from cystic fibrosis cells

A hallmark feature of cystic fibrosis (CF) is progressive pulmonary obstruction arising from exaggerated host proinflammatory responses to chronic bacterial airway colonization. The mechanisms for these heightened inflammatory responses have been only partially characterized, hampering development o...

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Veröffentlicht in:The Journal of immunology (1950) 2013-02, Vol.190 (3), p.1227-1238
Hauptverfasser: Mayer, Matthew L, Blohmke, Christoph J, Falsafi, Reza, Fjell, Chris D, Madera, Laurence, Turvey, Stuart E, Hancock, Robert E W
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container_issue 3
container_start_page 1227
container_title The Journal of immunology (1950)
container_volume 190
creator Mayer, Matthew L
Blohmke, Christoph J
Falsafi, Reza
Fjell, Chris D
Madera, Laurence
Turvey, Stuart E
Hancock, Robert E W
description A hallmark feature of cystic fibrosis (CF) is progressive pulmonary obstruction arising from exaggerated host proinflammatory responses to chronic bacterial airway colonization. The mechanisms for these heightened inflammatory responses have been only partially characterized, hampering development of effective anti-inflammatory therapies. The aim of this study was to identify and validate novel dysfunctional processes or pathways driving the hyperinflammatory phenotype of CF cells using systems biology and network analysis to examine transcriptional changes induced by innate defense regulator (IDR)-1018, an anti-inflammatory peptide. IDR-1018 selectively attenuated hyperinflammatory cytokine production from CF airway cells and PBMCs stimulated with multiple bacterial ligands, including flagellin (FliC). Network analysis of CF cell transcriptional responses to FliC and IDR-1018 identified dysfunctional autophagy as the target of the peptide via modulation of upstream adenosine monophosphate-activated protein kinase (AMPK)-Akt signaling. After treatment with FliC, CF cells were found to have elevated levels of the autophagosome marker LC3-II, and GFP-LC3-transfected CF airway cells showed abnormal perinuclear accumulation of GFP(+) structures. In both instances, treatment of CF cells with IDR-1018 abolished the accumulation of LC3 induced by FliC. Furthermore, inhibition of autophagosome-lysosome fusion with bafilomycinA1 attenuated the anti-inflammatory and autophagosome-clearing effects of IDR-1018, as did a chemical inhibitor of Akt and an activator of AMPK. These findings were consistent with hypotheses generated in silico, demonstrating the utility of systems biology and network analysis approaches for providing pathway-level insights into CF-associated inflammation. Collectively, these data suggest that dysfunctional autophagosome clearance contributes to heightened inflammatory responses from CF transmembrane receptor mutant cells and highlight autophagy and AMPK-Akt signaling as novel anti-inflammatory targets in CF.
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The mechanisms for these heightened inflammatory responses have been only partially characterized, hampering development of effective anti-inflammatory therapies. The aim of this study was to identify and validate novel dysfunctional processes or pathways driving the hyperinflammatory phenotype of CF cells using systems biology and network analysis to examine transcriptional changes induced by innate defense regulator (IDR)-1018, an anti-inflammatory peptide. IDR-1018 selectively attenuated hyperinflammatory cytokine production from CF airway cells and PBMCs stimulated with multiple bacterial ligands, including flagellin (FliC). Network analysis of CF cell transcriptional responses to FliC and IDR-1018 identified dysfunctional autophagy as the target of the peptide via modulation of upstream adenosine monophosphate-activated protein kinase (AMPK)-Akt signaling. After treatment with FliC, CF cells were found to have elevated levels of the autophagosome marker LC3-II, and GFP-LC3-transfected CF airway cells showed abnormal perinuclear accumulation of GFP(+) structures. In both instances, treatment of CF cells with IDR-1018 abolished the accumulation of LC3 induced by FliC. Furthermore, inhibition of autophagosome-lysosome fusion with bafilomycinA1 attenuated the anti-inflammatory and autophagosome-clearing effects of IDR-1018, as did a chemical inhibitor of Akt and an activator of AMPK. These findings were consistent with hypotheses generated in silico, demonstrating the utility of systems biology and network analysis approaches for providing pathway-level insights into CF-associated inflammation. 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After treatment with FliC, CF cells were found to have elevated levels of the autophagosome marker LC3-II, and GFP-LC3-transfected CF airway cells showed abnormal perinuclear accumulation of GFP(+) structures. In both instances, treatment of CF cells with IDR-1018 abolished the accumulation of LC3 induced by FliC. Furthermore, inhibition of autophagosome-lysosome fusion with bafilomycinA1 attenuated the anti-inflammatory and autophagosome-clearing effects of IDR-1018, as did a chemical inhibitor of Akt and an activator of AMPK. These findings were consistent with hypotheses generated in silico, demonstrating the utility of systems biology and network analysis approaches for providing pathway-level insights into CF-associated inflammation. 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subjects Anti-Inflammatory Agents - pharmacology
Antimicrobial Cationic Peptides - pharmacology
Autophagy - drug effects
Cell Line
Child
Cystic Fibrosis - immunology
Cystic Fibrosis - pathology
Cytokines - biosynthesis
Cytokines - genetics
Epithelial Cells - drug effects
Epithelial Cells - immunology
Epithelial Cells - pathology
Escherichia coli Proteins - immunology
Flagellin
Gene Expression Regulation - drug effects
Humans
Inflammation
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - immunology
Leukocytes, Mononuclear - metabolism
Lung - pathology
Lysosomes - drug effects
Lysosomes - physiology
Macrolides - pharmacology
Microtubule-Associated Proteins - biosynthesis
Microtubule-Associated Proteins - genetics
Models, Immunological
Protein Kinases - physiology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - physiology
Signal Transduction - drug effects
Systems Biology
Transcription, Genetic - drug effects
title Rescue of dysfunctional autophagy attenuates hyperinflammatory responses from cystic fibrosis cells
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