Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
14 06 2023
14 06 2023
Historique:
received:
22
11
2022
accepted:
01
06
2023
medline:
16
6
2023
pubmed:
15
6
2023
entrez:
14
6
2023
Statut:
epublish
Résumé
In mammals, the ORMDL family of evolutionarily conserved sphingolipid regulators consists of three highly homologous members, ORMDL1, ORMDL2 and ORMDL3. ORMDL3 gene has been associated with childhood-onset asthma and other inflammatory diseases in which mast cells play an important role. We previously described increased IgE-mediated activation of mast cells with simultaneous deletions of ORMDL2 and ORMDL3 proteins. In this study, we prepared mice with Ormdl1 knockout and thereafter, produced primary mast cells with reduced expression of one, two or all three ORMDL proteins. The lone deletion of ORMDL1, or in combination with ORMDL2, had no effect on sphingolipid metabolism nor IgE-antigen dependent responses in mast cells. Double ORMDL1 and ORMDL3 knockout mast cells displayed enhanced IgE-mediated calcium responses and cytokine production. Silencing of ORMDL3 in mast cells after maturation increased their sensitivity to antigen. Mast cells with reduced levels of all three ORMDL proteins demonstrated pro-inflammatory responses even in the absence of antigen activation. Overall, our results show that reduced levels of ORMDL proteins shift mast cells towards a pro-inflammatory phenotype, which is predominantly dependent on the levels of ORMDL3 expression.
Identifiants
pubmed: 37316542
doi: 10.1038/s41598-023-36344-5
pii: 10.1038/s41598-023-36344-5
pmc: PMC10267218
doi:
Substances chimiques
Sphingolipids
0
Immunoglobulin E
37341-29-0
ORMDL3 protein, mouse
0
Membrane Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9615Informations de copyright
© 2023. The Author(s).
Références
Cell Mol Life Sci. 2016 Mar;73(6):1265-85
pubmed: 26407610
Nature. 1970 Aug 15;227(5259):680-5
pubmed: 5432063
Sci Rep. 2017 Aug 15;7(1):8164
pubmed: 28811536
Nature. 2010 Feb 25;463(7284):1048-53
pubmed: 20182505
Annu Rev Biophys Biomol Struct. 2003;32:183-206
pubmed: 12574066
J Immunol. 2005 Feb 1;174(3):1153-8
pubmed: 15661867
J Vis Exp. 2015 May 27;(99):e52753
pubmed: 26068439
J Lipid Res. 2021;62:100121
pubmed: 34560079
Genome Biol. 2002;3(6):RESEARCH0027
pubmed: 12093374
Eur J Immunol. 1981 Jun;11(6):527-9
pubmed: 6790293
Immunol Rev. 2018 Mar;282(1):73-86
pubmed: 29431203
Chem Immunol Allergy. 2010;95:45-66
pubmed: 20519881
Front Immunol. 2021 Feb 19;12:604974
pubmed: 33679742
Adv Immunol. 2008;98:85-120
pubmed: 18772004
J Lipid Res. 2021;62:100082
pubmed: 33939982
Cell Res. 2011 Jan;21(1):6-21
pubmed: 21135871
N Engl J Med. 2010 Sep 23;363(13):1211-1221
pubmed: 20860503
J Immunol Methods. 2007 Jan 10;318(1-2):11-9
pubmed: 17141265
J Allergy Clin Immunol. 2015 Oct;136(4):1035-46.e6
pubmed: 25842287
Eur J Immunol. 2010 Jul;40(7):1843-51
pubmed: 20583030
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5851-6
pubmed: 20212121
BMC Bioinformatics. 2006 Mar 09;7:123
pubmed: 16526949
J Lipid Res. 2016 Aug;57(8):1412-22
pubmed: 27313060
Cytometry A. 2004 Sep;61(1):62-8
pubmed: 15351990
Adv Exp Med Biol. 2011;716:186-211
pubmed: 21713658
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1483-1494
pubmed: 31176037
Adv Exp Med Biol. 2010;688:1-23
pubmed: 20919643
J Leukoc Biol. 2013 Nov;94(5):1013-24
pubmed: 23904439
J Biol Chem. 2012 Nov 23;287(48):40198-204
pubmed: 23066021
Nat Struct Mol Biol. 2021 Mar;28(3):240-248
pubmed: 33558761
Nat Med. 2015 Sep;21(9):1028-1037
pubmed: 26301690
J Biol Chem. 2015 Jan 30;290(5):2822-30
pubmed: 25519910
Dev Cell. 2018 Aug 6;46(3):327-343.e7
pubmed: 30086303
Thorax. 2004 Jun;59(6):459-64
pubmed: 15170023
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12911-6
pubmed: 14569021
Eur J Immunol. 2001 Jan;31(1):1-10
pubmed: 11169432
Hum Mol Genet. 2010 Jan 1;19(1):111-21
pubmed: 19819884
J Allergy Clin Immunol. 2006 Jun;117(6):1277-84
pubmed: 16750987
J Immunol. 1981 Aug;127(2):788-94
pubmed: 7019332
Nature. 2007 Jul 26;448(7152):470-3
pubmed: 17611496
J Biol Chem. 2022 Feb;298(2):101517
pubmed: 34942147
J Lipid Res. 2009 Apr;50 Suppl:S423-8
pubmed: 19095631
Nat Commun. 2013;4:2479
pubmed: 24056518
Immunol Invest. 2019 Apr;48(3):303-320
pubmed: 30335529
Nat Med. 2012 May 04;18(5):693-704
pubmed: 22561833
Nat Rev Mol Cell Biol. 2018 Mar;19(3):175-191
pubmed: 29165427
Elife. 2019 Dec 27;8:
pubmed: 31880535
Nat Prod Rep. 2018 Sep 19;35(9):921-954
pubmed: 29863195
EMBO Rep. 2023 Jan 9;24(1):e54689
pubmed: 36408842
Allergy. 2016 Jul;71(7):918-30
pubmed: 26969910
Nat Immunol. 2016 Jul;17(7):878-87
pubmed: 27135604
Front Immunol. 2021 Feb 11;11:591975
pubmed: 33643282
Front Immunol. 2017 May 22;8:587
pubmed: 28588581
Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3728-33
pubmed: 25775599
Immun Inflamm Dis. 2021 Dec;9(4):1394-1405
pubmed: 34288557
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16648-53
pubmed: 23011799