Acid Sphingomyelinase Amplifies Redox Signaling in <i>Pseudomonas aeruginosa</i>-Induced Macrophage Apoptosis

Zhang, Yang; Li, Xiang; Carpinteiro, Alexander; Gulbins, Erich

doi:10.4049/jimmunol.181.6.4247

Cited by 91 publications

(116 citation statements)

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“…We have recently demonstrated that ceramide plays a critical role in the development of cystic fibrosis and the high sensitivity of Cftr -deficient mice to P. aeruginosa infections [11, 20]. Employing biochemical, fluorescence microscopy and mass spectrometry techniques, we revealed an accumulation of ceramide in lungs, in particular in epithelial cells of large and small bronchi, in different Cftr -deficient mouse strains (Fig.…”

Section: Ceramide In Cystic Fibrosismentioning

confidence: 86%

“…Previous studies published by our group indicate that P. aeruginosa infection of epithelial cells and macrophages activates the acid sphingomyelinase and triggers a translocation of the enzyme onto the extracellular leaflet of the cell membrane [19, 20]. The activity of the acid sphingomyelinase triggers the formation of ceramide-enriched membrane platforms in the outer leaflet.…”

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 96%

“…In vivo studies indicate that stimulation of CD95 and, thus, presumably induction of apoptosis in epithelial cells is central for a coordinated defense against pulmonary P. aeruginosa infections. It might be possible that the induction of apoptosis in epithelial cells modulates the local immune response to the pathogen and prevents an over-exaggerated release of cytokines [19, 20]. Studies from Kumar et al .…”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

“…The activity of the acid sphingomyelinase triggers the formation of ceramide-enriched membrane platforms in the outer leaflet. Activation of the acid sphingomyelinase is mediated by reactive oxygen species, at least in macrophages [20]. Recent studies demonstrate that activation of the acid sphingomyelinase is defective in cells lacking Cftr [85].…”

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 99%

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The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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Section: Ceramide In Cystic Fibrosismentioning

confidence: 86%

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 96%

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

Section: P Aeruginosa Infections and Ceramidementioning

confidence: 99%

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The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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“…Ceramide may regulate neurogenesis via several pathways: Ceramide controls activity of Akt shown to be important for neuronal proliferation 21 . Ceramide has been also shown to regulate the formation of reactive oxygen species via activation of NADPH oxidases 22 , to mediate the effects of the cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α [23][24][25] and to regulate stress-activated kinases 26 and calcium release 27 . Thus, ceramide may coordinate negative effects on hippocampal neurons by Akt inhibition and assembling of molecules involved in oxidative stress, proinflammatory receptors and stress-signaling.…”

Section: A-d)mentioning

confidence: 99%

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

Gulbins

Palmada

Reichel

et al. 2013

Nat Med

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336

451

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Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants. DOI: https://doi.org/10. 1038/nm.3214 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-79905 Accepted Version Originally published at: Gulbins, E; Palmada, M; Reichel, M; Lüth, A; Böhmer, C; Amato, D; Müller, C P; Tischbirek, C H; Groemer, T W; Tabatabai, G; Becker, K A; Tripal, P; Staedtler, S; Ackermann, T F; van Brederode, J; Alzheimer, C; Weller, M; Lang, U E; Kleuser, B; Grassme, H; Kornhuber, J (2013). Acid sphingomyelinaseceramide system mediates effects of antidepressant drugs. Nature Medicine, 19 (7) Major depression may be triggered by psychological stress, inflammatory cytokines, and dysfunction of the hypothalamic-pituitary-adrenal axis, etc. 1-4 .The previously held monoamine hypothesis for the action of antidepressants has been questioned because the antidepressant effect of these drugs is not clearly associated with their monoaminergic effect; in fact, the antidepressant tianeptine is even a serotonin reuptake enhancer 5 . Furthermore, the direct effect on monoamines contrasts with the delay of antidepressant effects in patients. Recent concepts of the pathogenesis of major depression suggest a change of cellular plasticity predominantly in the hippocampus and a shift in the balance between neurogenic and antiapoptotic events that leads to neurodegeneration and hippocampal atrophy [6][7][8][9] . Antidepressants increase neurogenesis and reverse hippocampal atrophy associated with major depression 9 .Here, we tested the role of the acid sphingomyelinase (EC 3.1.4.12, sphingomyelin phosphodiesterase, human protein: ASM, murine protein: Asm, gene symbol: Smpd1) and ceramide system as a target for antidepressants. Asm is ubiquitously expressed and releases ceramide from sphingomyelin, predominantly in lysosomes but also in secretory lysosomes and on the plasma membrane 10-13 .The antidepres...

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Interactions of meningococcal virulence factors with endothelial cells at the human blood–cerebrospinal fluid barrier and their role in pathogenicity

Simonis

Schubert‐Unkmeir

2016

FEBS Letters

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Edited by Wilhelm JustThe Gram-negative extracellular bacterium Neisseria meningitidis is one of the most common aetiological agents of bacterial meningitis affecting predominantly young children worldwide. This bacterium is normally a quiescent coloniser of the upper respiratory tract, but in some individuals it enters the blood stream and causes invasive diseases, such as septicaemia and meningitis. Interactions of N. meningitidis with human endothelial cells are crucially involved in pathogencitiy, and great efforts have been made to understand these molecular interactions. The aim of this review article is to provide an overview of the interactions of meningococcal virulence factors with host endothelial cells at the blood-cerebrospinal fluid barrier.

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Acid Sphingomyelinase Amplifies Redox Signaling in Pseudomonas aeruginosa-Induced Macrophage Apoptosis

Cited by 91 publications

References 38 publications

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

Interactions of meningococcal virulence factors with endothelial cells at the human blood–cerebrospinal fluid barrier and their role in pathogenicity

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