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Oroscomucoid like protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide  Marina Miller,

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Presentation on theme: "Oroscomucoid like protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide  Marina Miller,"— Presentation transcript:

1 Oroscomucoid like protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide  Marina Miller, MD, PhD, Peter Rosenthal, BS, Andrew Beppu, BS, Ruth Gordillo, PhD, David H. Broide, MB, ChB  Journal of Allergy and Clinical Immunology  Volume 139, Issue 4, Pages e4 (April 2017) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Levels of serum sphingolipids in hORMDL3zp3−Cre mice. Levels of serum sphingolipids in hORMDL3zp3−Cre mice and WT mice were quantitated by LC-MS/MS. hORMDL3zp3−Cre mice had significantly reduced serum levels of sphingolipids including (A) sphinganine (P < .02), (B) ceramide 24:0 (P < .01), (C) sphingosine (P < .02), and (D) S1P (P < .02) compared with WT control. LC-MS/MS, Liquid chromatography-tandem mass spectrometry. Fig 1, A, C, and D: **P < .02. Fig 1, B: **P < .01. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 S1P increases AHR in hORMDL3zp3−Cre mice. A, Administration of intranasal S1P, 10 ng on day 0, and 10 ng on day 7, to hORMDL3zp3−Cre mice significantly increases AHR compared with hORMDL3zp3−Cre mice not administered S1P (P < .05), or compared with WT mice administered S1P (P < .05). No allergen was administered to any group of mice. Levels of peribronchial MBP+ eosinophils (B), CD4+ cells (C), and F4/80+ macrophages (D) were quantitated by immunohistochemistry in lung sections. MBP, Major basic protein. ***P < .05. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 ORMDL3 inhibits the enzyme SPT, which regulates the first step of sphingolipid synthesis (conversion of serine and palmitoyl-coA to 5-keto-sphingosine) as described.E15 5-Keto-sphingosine is metabolized through intermediary steps (sphinganine, dihydroceramide, ceramide, and sphingosine) to S1P. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E2 Levels of serum ceramide in hORMDL3zp3−Cre mice. Levels of serum ceramides in hORMDL3zp3−Cre mice and WT mice were quantitated by LC-MS/MS. Levels of only serum ceramide 24:0 (P < .01) (Fig 1) (but not ceramide 18:0 [A], ceramide 20:0 [B], ceramide 22:0 [C], and ceramide 24:1 [D]) (Fig E1) were decreased in serum in hORMDL3zp3−Cre mice compared with WT control. LC-MS/MS, Liquid chromatography-tandem mass spectrometry. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E3 Levels of lung sphingolipids in hORMDL3zp3−Cre mice. Levels of lung sphingolipids in hORMDL3zp3−Cre mice and WT mice were quantitated by LC-MS/MS. hORMDL3zp3−Cre mice had significantly reduced lung levels of sphinganine (P < .05) (A), but no reduction in ceramide 24:0 (B), sphingosine (C), or S1P (D) compared with WT control. LC-MS/MS, Liquid chromatography-tandem mass spectrometry. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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