The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice.
Alternaria alternata
Asthma
ORMDL3
ceramides
house dust mite
sphingolipids
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
20
02
2019
revised:
27
06
2019
accepted:
28
06
2019
pubmed:
23
7
2019
medline:
9
6
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk. We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma. Ormdl3-LacZ reporter mice, gene-deficient Ormdl3 HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3 ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma.
Sections du résumé
BACKGROUND
Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk.
OBJECTIVE
We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma.
METHODS
Ormdl3-LacZ reporter mice, gene-deficient Ormdl3
RESULTS
HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3
CONCLUSION
ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma.
Identifiants
pubmed: 31330218
pii: S0091-6749(19)30943-1
doi: 10.1016/j.jaci.2019.06.041
pmc: PMC7610749
mid: EMS123577
pii:
doi:
Substances chimiques
Ceramides
0
Cytokines
0
Membrane Proteins
0
ORMDL3 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1648-1659.e9Subventions
Organisme : European Research Council
ID : 789384
Pays : International
Organisme : European Research Council
ID : 819314
Pays : International
Informations de copyright
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Références
Int J Biochem Cell Biol. 2017 Jun;87:8-17
pubmed: 28336364
Cell Mol Life Sci. 2016 Mar;73(6):1265-85
pubmed: 26407610
Curr Protoc Mouse Biol. 2016 Jun 01;6(2):169-184
pubmed: 27248433
J Allergy Clin Immunol. 2015 Oct;136(4):1035-46.e6
pubmed: 25842287
N Engl J Med. 2008 Nov 6;359(19):1985-94
pubmed: 18923164
Nat Commun. 2013;4:2479
pubmed: 24056518
J Allergy Clin Immunol. 2018 Sep;142(3):749-764.e3
pubmed: 29307657
J Allergy Clin Immunol. 2017 Apr;139(4):1373-1376.e4
pubmed: 27826095
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18706-11
pubmed: 20937879
Genome Biol. 2002;3(6):RESEARCH0027
pubmed: 12093374
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16648-53
pubmed: 23011799
Allergy. 2013 Feb;68(2):204-12
pubmed: 23253209
Biochim Biophys Acta. 2005 Oct 15;1737(1):44-51
pubmed: 16216550
Am J Respir Crit Care Med. 2019 Feb 15;199(4):478-488
pubmed: 30339462
J Allergy Clin Immunol. 2013 Feb;131(2):501-11.e1
pubmed: 22939756
Am J Physiol Lung Cell Mol Physiol. 2012 Apr 15;302(8):L736-45
pubmed: 22287614
J Allergy Clin Immunol. 2018 Jun;141(6):2282-2286.e6
pubmed: 29374573
J Pharmacol Exp Ther. 2008 Feb;324(2):548-57
pubmed: 18042827
J Allergy Clin Immunol. 2017 Jul;140(1):76-88.e7
pubmed: 27746238
Methods Mol Biol. 2018;1799:183-210
pubmed: 29956153
N Engl J Med. 2013 Sep 5;369(10):976-8
pubmed: 24004126
Mol Immunol. 2002 Sep;38(16-18):1239-45
pubmed: 12217390
Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19222-7
pubmed: 22080611
Sci Transl Med. 2013 May 22;5(186):186ra67
pubmed: 23698380
J Clin Invest. 2013 Apr;123(4):1784-97
pubmed: 23549085
Nat Rev Immunol. 2016 Jul;16(7):449-62
pubmed: 27320317
J Allergy Clin Immunol. 2011 Jun;127(6):1587-94.e6
pubmed: 21546069
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5851-6
pubmed: 20212121
Hum Immunol. 2014 Sep;75(9):960-7
pubmed: 25167772
Allergy Asthma Clin Immunol. 2013 Feb 01;9(1):4
pubmed: 23369242
N Engl J Med. 2013 Apr 11;368(15):1398-407
pubmed: 23534543
Curr Opin Clin Nutr Metab Care. 2017 Mar;20(2):99-103
pubmed: 28030368
J Immunol. 2014 Apr 15;192(8):3475-87
pubmed: 24623133
Am J Respir Crit Care Med. 2016 Apr 15;193(8):889-97
pubmed: 26575599
J Biol Chem. 2012 Nov 23;287(48):40198-204
pubmed: 23066021
J Immunol. 2017 Apr 15;198(8):3017-3022
pubmed: 28275141
Nature. 2010 Feb 25;463(7284):1048-53
pubmed: 20182505
Neurology. 2017 Feb 7;88(6):533-542
pubmed: 28077491
Biochim Biophys Acta. 2009 Apr;1791(4):297-306
pubmed: 19416652
J Biol Chem. 2015 Jan 30;290(5):2822-30
pubmed: 25519910
J Allergy Clin Immunol. 2015 Apr;135(4):1008-1018.e1
pubmed: 25512083
Mol Biol Cell. 2013 Mar;24(6):870-81
pubmed: 23363605
J Allergy Clin Immunol. 2015 Oct;136(4):893-903.e14
pubmed: 25930191
Hum Mol Genet. 2010 Jan 1;19(1):111-21
pubmed: 19819884
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5701-2
pubmed: 20304791
Science. 2015 Sep 4;349(6252):1106-10
pubmed: 26339029
Nature. 2007 Jul 26;448(7152):470-3
pubmed: 17611496
Cytometry A. 2015 Jul;87(7):636-45
pubmed: 25573116
Mol Biol Cell. 2012 Jun;23(12):2388-98
pubmed: 22535525
J Allergy Clin Immunol. 2017 May;139(5):1496-1507.e3
pubmed: 27623174
FASEB J. 2016 Dec;30(12):4289-4300
pubmed: 27645259
Nat Immunol. 2017 Sep 19;18(10):1076-1083
pubmed: 28926539
Adv Bioinformatics. 2008;2008:420747
pubmed: 19956698
Hum Mol Genet. 2013 Feb 1;22(3):519-30
pubmed: 23100328
Biochem Biophys Res Commun. 1995 Jun 15;211(2):396-403
pubmed: 7794249
Immunity. 2016 Sep 20;45(3):669-684
pubmed: 27637149
J Allergy Clin Immunol. 2016 Mar;137(3):758-66.e3
pubmed: 26483175
Nat Commun. 2016 Nov 16;7:13426
pubmed: 27848966