New insights on the role of ceramide 1-phosphate in inflammation

Gómez-Muñoz, Antonio; Gangoiti, Patricia; Arana, Lide; Ouro, Alberto; Rivera, Io-Guané; Ordoñez, Marta; Trueba, Miguel

doi:10.1016/j.bbalip.2013.02.001

Cited by 54 publications

(42 citation statements)

References 110 publications

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“…Such treatments are considered to affect the lateral diffusion, aggregation, and function of receptor complexes (37). Bioactive lipids, such as ceramides and sphingosine 1-phosphate, are known to regulate inflammation in cells and to activate several signaling pathways (38). Therefore, it is reasonable to infer that HP-b-CD activates the innate immune response and exerts its adjuvant activity by modifying these lipid-dependent biological processes.…”

Section: Discussionmentioning

confidence: 99%

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Onishi

Ozasa

Kobiyama

et al. 2015

The Journal of Immunology

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Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines.

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Section: Discussionmentioning

confidence: 99%

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Onishi

Ozasa

Kobiyama

et al. 2015

The Journal of Immunology

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“…It is remarkable that while the role of S1P and S1P receptor-agonists/antagonists in the pathogenesis of inflammatory disorders has been extensively studied in vivo using translational mouse models of human diseases [9,10,25], the knowledge concerning the function of exogenous C1P in modulating immune responses is, at present, mostly limited to in vitro observations [26,27]. Both pro-and anti-inflammatory behaviour of exogenous C1P has been described.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, our observation that C1P inhibits CS-induced IL-8 production in AECs and neutrophils further strengthens our assumption that C1P might be a new therapeutic target for COPD. The potential of C1P to dampen pro-inflammatory cytokine production has also been reported for LPS-induced TNF-α, MIP-2, IL-6 and IL-8 in human embryonic kidney cells, human blood mononuclear cells, endothelial cells and mastocytes [27,33,37].…”

Section: Figurementioning

confidence: 99%

Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation

et al. 2015

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Sphingolipids are involved in the pathogenesis of inflammatory diseases. The central molecule is ceramide, which can be converted into ceramide-1-phosphate (C1P). Although C1P can exert anti-and pro-inflammatory effects, its influence on cigarette smoke (CS)-induced lung inflammation is unknown. We aimed to clarify the role of C1P in the pathogenesis of CS-triggered pulmonary inflammation and emphysema in humans and mice.The effects of C1P were addressed on CS-induced lung inflammation in C57BL/6 mice, CS extracttriggered activation of human airway epithelial cells (AECs) and neutrophils from patients with chronic obstructive pulmonary disease. Differential cell counts in bronchoalveolar lavage fluid were determined by flow cytometry and pro-inflammatory cytokines were measured by ELISA. Expression and DNA binding of nuclear factor (NF)-κB and neutral sphingomyelinase (nSMase) were quantified by PCR, electrophoretic mobility shift and fluorometric assays.C1P reduced CS-induced acute and chronic lung inflammation and development of emphysema in mice, which was associated with a reduction in nSMase and NF-κB activity in the lungs. nSMase activity in human serum correlated negatively with forced expiratory volume in 1 s % predicted. In human AECs and neutrophils, C1P inhibited CS-induced activation of NF-κB and nSMase, and reduced pro-inflammatory cytokine release.Our results suggest that C1P is a potential target for anti-inflammatory treatment in CS-induced lung inflammation. @ERSpublications Ceramide-1-phosphate, a potential target for anti-inflammatory treatment in cigarette smokeinduced lung inflammation

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“…A predominant metabolite of ceramide is ceramide-1-phosphate (C1P), which can be formed via the phosphorylation of ceramide by ceramide kinase (25,26). The C1P receptor is coupled to inhibitory guanine nucleotide-binding regulatory (Gi) proteins and causes the activation of the PI3K/Akt signaling pathway to facilitate cell survival (25,27,28).…”

Section: Discussionmentioning

confidence: 99%

Cellular Uptake of Clostridium botulinum C2 Toxin Requires Acid Sphingomyelinase Activity

et al. 2017

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Clostridium botulinum C2 toxin consists of an enzyme component (C2I) and a binding component (C2II). Activated C2II (C2IIa) binds to a cell receptor, giving rise to lipid raft-dependent oligomerization, and it then assembles with C2I. The whole toxin complex is then endocytosed into the cytosol, resulting in the destruction of the actin cytoskeleton and cell rounding. Here, we showed that C2 toxin requires acid sphingomyelinase (ASMase) activity during internalization. In this study, inhibitors of ASMase and lysosomal exocytosis blocked C2 toxin-induced cell rounding. C2IIa induced Ca 2ϩ influx from the extracellular medium to cells. C2 toxininduced cell rounding was enhanced in the presence of Ca 2ϩ . ASMase was released extracellularly when cells were incubated with C2IIa in the presence of Ca 2ϩ . Small interfering RNA (siRNA) knockdown of ASMase reduced C2 toxin-induced cell rounding. ASMase hydrolyzes sphingomyelin to ceramide on the outer leaflet of the membrane at acidic pH. Ceramide was detected in cytoplasmic vesicles containing C2IIa. These results indicated that ASMase activity is necessary for the efficient internalization of C2 toxin into cells. Inhibitors of ASMase may confer protection against infection.

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New insights on the role of ceramide 1-phosphate in inflammation

Cited by 54 publications

References 110 publications

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation

Cellular Uptake of Clostridium botulinum C2 Toxin Requires Acid Sphingomyelinase Activity

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