Defective Acid Sphingomyelinase Pathway with <i>Pseudomonas aeruginosa</i> Infection in Cystic Fibrosis

Yu, Hong; Zeidan, Youssef H.; Wu, Bill X.; Jenkins, Russell W.; Flotte, Terence R.; Hannun, Yusuf A.; Virella‐Lowell, Isabel

doi:10.1165/rcmb.2008-0295oc

Cited by 53 publications

(60 citation statements)

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“…Indeed, we observed a marked chronic accumulation of ceramide in Cftr-deficient alveolar macrophages. In addition, Cftr deficiency prevented the acute and rapid activation of acid sphingomyelinase observed in WT cells postinfection with P. aeruginosa (15), thereby preventing the acute release of ceramide on infection. On the basis of these observations, we assume that the LysoSensor Green DND-189-positive lysosomes are secretory lysosomes containing the signaling pool of acid sphingomyelinase, that their vesicular pH is regulated by Cftr and that the increase in the pH of secretory lysosomes prevents activation of the acid sphingomyelinase.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, ceramide is acutely released by the acid sphingomyelinase on infection of wild-type (WT) mice or cells with P. aeruginosa infection (13)(14)(15). In lung alveolar macrophages, P. aeruginosa infection triggers the rapid formation of ceramideenriched membrane platforms, which cluster and stimulate the activity of NADPH oxidase, thereby resulting in a release of reactive oxygen species (ROS) (14).…”

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confidence: 99%

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Alterations in Ceramide Concentration and pH Determine the Release of Reactive Oxygen Species by Cftr-Deficient Macrophages on Infection

Zhang

Grassmé

et al. 2010

The Journal of Immunology

106

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We recently demonstrated that the accumulation of ceramide in Cftr-deficient epithelial cells is important for the pathophysiology of CF. However, the role of ceramide in other lung cells, particularly lung macrophages, requires definition. In this study, we report that ceramide is accumulated in Cftr-deficient lung macrophages. Alveolar macrophages contain a vesicle population, which is stained with LysoSensor probes but not by tetramethylrhodamine dextran. These vesicles, presumably secretory lysosomes, exhibit a higher pH in Cftr-deficient macrophages than the corresponding vesicles in lung macrophages isolated from wild-type (WT) mice. Alkalinization of these vesicles in Cftr-deficient macrophages correlates with a failure of the macrophages to respond to infection with various Pseudomonas aeruginosa strains by acutely activating acid sphingomyelinase, releasing ceramide, forming ceramide-enriched membrane platforms that serve to cluster gp91phox, and, most importantly, releasing reactive oxygen species (ROS). In contrast, these events occur rapidly in WT lung macrophages postinfection. Inhibiting ROS in WT macrophages prevents the killing of P. aeruginosa. These findings provide evidence for a novel pH-controlled pathway from acid sphingomyelinase activation via ceramide and clustering of gp91phox to the release of ROS in lung macrophages.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

Alterations in Ceramide Concentration and pH Determine the Release of Reactive Oxygen Species by Cftr-Deficient Macrophages on Infection

Zhang

Grassmé

et al. 2010

The Journal of Immunology

106

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“…4, A .a induced the de novo synthesis of dhSph, dhCer, and ceramide. Previous studies have shown that Pseudomonas aeruginosa ( 23,24 ) and Neisseria gonorrheae ( 25 ) activated acid SMase at early time points (5-45 min). Our previous study also demonstrated that P .…”

Section: Fenretinide Inhibited Il-1 ␤ Il-6 and Pge2 Cytokine Exprementioning

confidence: 94%

“…Previous studies have shown that bacteria induced ceramide generation by the SMase pathway (23)(24)(25), but the effect of A . a on sphingolipid metabolism has not been determined.…”

Section: A a Stimulated The De Novo Synthesis Of Ceramidementioning

confidence: 95%

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Valerio

Bielawski

2013

Journal of Lipid Research

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Sphingolipids play important roles in regulating cell growth, death, senescence, adhesion, migration, infl ammation, angiogenesis, and intracellular traffi cking. Among the sphingolipids, ceramides have been recognized as "second messengers" in modulating immune signaling transduction ( 1 ). Ceramides can be generated via three pathways ( 2 ) ( Fig. 1 ). The fi rst pathway is a de novo pathway, which occurs in the endoplasmic reticulum (ER) and possibly at ER-associated membranes, such as the perinuclear membrane and mitochondria-associated membranes. De novo synthesis of ceramides begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine by serine-palmitoyl transferase (SPT). 3-Keto-dihydrosphingosine is reduced to dihydrosphingosine (dhSph) and followed by acylation to produce dihydroceramide (dhCer). Finally, dhCer is catalyzed by dihydroceramide desaturase (DEGS) to generate ceramides. The second pathway is the sphingomyelinase (SMase) pathway, which occurs in the plasma membrane and the endosomal/lysosomal compartments. Ceramides are generated by hydrolysis of sphingomyelin (SM) by SMase. The third pathway is the salvage pathway, which occurs in the acidic subcellular compartments, such as the late endosomes and the lysosomes. In the acidic subcellular compartments, complex sphingolipids and glycosphingolipids are degraded to form sphingosine (Sph). Sph can be converted to ceramides by ceramide synthase. Conversely, ceramides can Abstract Ceramides play an essential role in modulating immune signaling pathways and proinfl ammatory cytokine production in response to infectious pathogens, stress stimuli, or chemotherapeutic drugs. In this study, we demonstrated that Aggregatibacter actinomycetemcomitans , the path ogen for aggressive periodontitis, induced de novo synthesis of ceramide in Raw 264.7 cells. In addition, we identifi ed that fenretinide, a synthetic retinoid, suppressed the de novo synthesis of ceramide induced by A. actinomycetemcomitans. Moreover, fenretinide attenuated interleukin (IL)-1 ␤ , IL-6, and cyclooxygenase-2 mRNA expression induced by A. actinomycetemcomitans. Fenretinide also decreased IL-1 ␤ , IL-6, and prostaglandin E2 proinfl ammatory cytokine levels in Raw 264.7 cells induced by A. actinomycetemcomitans. However, fenretinide had no signifi cant effects on tumor necrosis factor alpha mRNA or protein levels. Furthermore, we showed that fenretinide inhibited the janus kinase-signal transducer and activator of transcription, phosphatidylinositol 3-kinase-Akt, protein kinase C, and nuclear factor-kappaB signaling pathways, whereas fenretinide up-regulated the mitogen-activated protein kinase signaling pathways after bacterial stimulation. This study emphasizes the de novo ceramide synthesis pathway in response to bacterial stimulation and demonstrates the anti-infl ammatory role of fenretinide in the bacteria-induced immune response.

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“…Other possible causes, such as genetic determinants, could influence individual levels of SLs (Hicks, 2009). In a different study, no significant difference has been found in basal ceramide levels in immortalised CF bronchial epithelial cells and lung homogenate from CFTR ko mice compared to wild type cells and mice (Yu, 2009). Very importantly, ceramide has been demonstrated to accumulate in the lower airways of CF patients and to be positively associated with neutrophilic inflammation (Brodlie, 2010), supporting the hypothesis that reduction of ceramide may be a therapeutic target for CF lung inflammation.…”

Section: Introductionmentioning

confidence: 90%

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

Dechecchi¹,

Nicolis²,

Mazzi³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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Defective Acid Sphingomyelinase Pathway with Pseudomonas aeruginosa Infection in Cystic Fibrosis

Cited by 53 publications

References 50 publications

Alterations in Ceramide Concentration and pH Determine the Release of Reactive Oxygen Species by Cftr-Deficient Macrophages on Infection

Alterations in Ceramide Concentration and pH Determine the Release of Reactive Oxygen Species by Cftr-Deficient Macrophages on Infection

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

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