ORMDL proteins regulate ceramide levels during sterile inflammation

Cai, Lin; Oyeniran, Clément; Biswas, Debolina D.; Allegood, Jeremy C.; Milstien, Sheldon; Kordula, Tomasz; Maceyka, Michael; Spiegel, Sarah

doi:10.1194/jlr.m065920

Cited by 43 publications

(58 citation statements)

References 35 publications

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“…Residues were reconstituted in 0.5 ml of starting mobile phase solvent for liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), sonicated, centrifuged, and clear supernatants transferred to autoinjector vials for analyses. Sphingolipids were separated by reverse-phase HPLC coupled to an AB Sciex 5500 quadrupole/linear ion trap (QTrap; SCIEX Framingham, MA) operating in triple quadrupole mode, as described previously [9]. …”

Section: Methodsmentioning

confidence: 99%

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Grenald

Doyle

Zhang

et al. 2017

Pain

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Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

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Section: Methodsmentioning

confidence: 99%

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Grenald

Doyle

Zhang

et al. 2017

Pain

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“…inflammatory mediators (31), and to cholesterol loading (32). Regulation of ORMDL gene expression has been described in response to viral infection (33,34) and by inflammatory and allergic stimuli (35)(36)(37).…”

Section: Ceramide Regulation Of the Ormdl/orm-spt Complexmentioning

confidence: 99%

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

Davis

Gable

Suemitsu

et al. 2019

Journal of Biological Chemistry

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Edited by George M. CarmanSphingolipids compose a lipid family critical for membrane structure as well as intra-and intercellular signaling. De novo sphingolipid biosynthesis is initiated by the enzyme serine palmitoyltransferase (SPT), which resides in the endoplasmic reticulum (ER) membrane. In both yeast and mammalian species, SPT activity is homeostatically regulated through small ER membrane proteins, the Orms in yeast and the ORMDLs in mammalian cells. These proteins form stable complexes with SPT. In yeast, the homeostatic regulation of SPT relies, at least in part, on phosphorylation of the Orms. However, this does not appear to be the case for the mammalian ORMDLs. Here, we accomplished a cell-free reconstitution of the sphingolipid regulation of the ORMDL-SPT complex to probe the underlying regulatory mechanism. Sphingolipid and ORMDL-dependent regulation of SPT was demonstrated in isolated membranes, essentially free of cytosol. This suggests that this regulation does not require soluble cytosolic proteins or small molecules such as ATP. We found that this system is particularly responsive to the pro-apoptotic sphingolipid ceramide and that this response is strictly stereospecific, indicating that ceramide regulates the ORMDL-SPT complex via a specific binding interaction. Yeast membranes harboring the Orm-SPT system also directly responded to sphingolipid, suggesting that yeast cells have, in addition to Orm phosphorylation, an additional Orm-dependent SPT regulatory mechanism. Our results indicate that ORMDL/Orm-mediated regulation of SPT involves a direct interaction of sphingolipid with the membrane-bound components of the SPT-regulatory apparatus. . 2 The abbreviations used are: LCB, long chain bases; SPT, serine palmitoyltransferase; scSPT, single chain SPT construct (SPTLC2-ssSPTa-SPTLC1 as a fusion protein in a single polypeptide); C(X), (phyto)ceramide-ceramide or phytoceramide, where X ϭ acyl chain length; TBS, Tris-buffered saline; PVDF, polyvinylidene difluoride.

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“…In perfect tune, clinical studies show that S1P levels significantly increase in bronchoalveolar lavage (BAL) of asthmatic patients following segmental allergen challenge and that this increase well correlates with pulmonary inflammation ( 9 ). In addition, genome-wide associated studies have linked Orm protein, negative regulators of sphingolipid metabolism to childhood onset asthma ( 10 , 11 ). S1P signaling has long been known to mediate lymphocyte trafficking in immunity and allergy by promoting lymphocytes migration ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Is Essential for the Expression of Sphingosine-1-Phosphate-Dependent Asthma-Like Disease in Mice

et al. 2017

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Sphingosine-1-phosphate (S1P) levels significantly increase in bronchoalveolar lavage (BAL) of asthmatic patients following segmental allergen challenge and this increase well correlates with pulmonary inflammation. Epidemiological, genetic, clinical, and experimental data indicate a potential for the toll-like receptor 4 (TLR4) to initiate and exacerbate allergic airway diseases. The aim of this study was to evaluate the contribution of TLR4 in S1P-dependent asthma-like disease in mice. BALB/c or TLR4 defective (C3H/HeJ) mice received S1P (10 ng/mouse), LPS (0.1 μg/mouse) or S1P + LPS. Furthermore, S1P-treated BALB/c mice were injected with the purified rabbit anti-TLR4 antibody (10 μg/mouse). S1P administration induced airway hyperreactivity and pulmonary inflammation associated to an increase in the percentage of dendritic cells (DCs) and macrophages into the lung of BALB/c mice. These effects were coupled to a reduction of DCs in the mediastinic lymph node. All these S1P-mediated effects were absent in TLR4 defective mice or reversed by treatment with a purified rabbit anti-TLR4 antibody. Confocal analysis of pulmonary sections showed a significant increase in TLR4+ cells and a similar presence of S1P1 and TLR4 following S1P challenge. Accordingly, the immunoprecipitation evidenced an increased S1P1/TLR4 interaction. In conclusion, our findings suggest that a functional interaction between S1P1 and TLR4 leads to an enhanced allergic inflammatory response. Thus, S1P pathway contributes to the sentinel role played by innate immunity providing new targets for prevention and treatment of allergic airway diseases.

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ORMDL proteins regulate ceramide levels during sterile inflammation

Cited by 43 publications

References 35 publications

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes

Toll-Like Receptor 4 Is Essential for the Expression of Sphingosine-1-Phosphate-Dependent Asthma-Like Disease in Mice

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