Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Mast Cells*/immunology ; Mast Cells*/metabolism ; Membrane Proteins*/genetics ; Membrane Proteins*/immunology ; Membrane Proteins*/metabolism; Animals ; Mice ; Antigen Presentation ; Immunoglobulin E ; Sphingolipids

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.
(© 2023. The Author(s).)

Cell Mol Life Sci. 2016 Mar;73(6):1265-85. (PMID: 26407610)
Nature. 1970 Aug 15;227(5259):680-5. (PMID: 5432063)
Sci Rep. 2017 Aug 15;7(1):8164. (PMID: 28811536)
Nature. 2010 Feb 25;463(7284):1048-53. (PMID: 20182505)
Annu Rev Biophys Biomol Struct. 2003;32:183-206. (PMID: 12574066)
J Immunol. 2005 Feb 1;174(3):1153-8. (PMID: 15661867)
J Vis Exp. 2015 May 27;(99):e52753. (PMID: 26068439)
J Lipid Res. 2021;62:100121. (PMID: 34560079)
Genome Biol. 2002;3(6):RESEARCH0027. (PMID: 12093374)
Eur J Immunol. 1981 Jun;11(6):527-9. (PMID: 6790293)
Immunol Rev. 2018 Mar;282(1):73-86. (PMID: 29431203)
Chem Immunol Allergy. 2010;95:45-66. (PMID: 20519881)
Front Immunol. 2021 Feb 19;12:604974. (PMID: 33679742)
Adv Immunol. 2008;98:85-120. (PMID: 18772004)
J Lipid Res. 2021;62:100082. (PMID: 33939982)
Cell Res. 2011 Jan;21(1):6-21. (PMID: 21135871)
N Engl J Med. 2010 Sep 23;363(13):1211-1221. (PMID: 20860503)
J Immunol Methods. 2007 Jan 10;318(1-2):11-9. (PMID: 17141265)
J Allergy Clin Immunol. 2015 Oct;136(4):1035-46.e6. (PMID: 25842287)
Eur J Immunol. 2010 Jul;40(7):1843-51. (PMID: 20583030)
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5851-6. (PMID: 20212121)
BMC Bioinformatics. 2006 Mar 09;7:123. (PMID: 16526949)
J Lipid Res. 2016 Aug;57(8):1412-22. (PMID: 27313060)
Cytometry A. 2004 Sep;61(1):62-8. (PMID: 15351990)
Adv Exp Med Biol. 2011;716:186-211. (PMID: 21713658)
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1483-1494. (PMID: 31176037)
Adv Exp Med Biol. 2010;688:1-23. (PMID: 20919643)
J Leukoc Biol. 2013 Nov;94(5):1013-24. (PMID: 23904439)
J Biol Chem. 2012 Nov 23;287(48):40198-204. (PMID: 23066021)
Nat Struct Mol Biol. 2021 Mar;28(3):240-248. (PMID: 33558761)
Nat Med. 2015 Sep;21(9):1028-1037. (PMID: 26301690)
J Biol Chem. 2015 Jan 30;290(5):2822-30. (PMID: 25519910)
Dev Cell. 2018 Aug 6;46(3):327-343.e7. (PMID: 30086303)
Thorax. 2004 Jun;59(6):459-64. (PMID: 15170023)
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12911-6. (PMID: 14569021)
Eur J Immunol. 2001 Jan;31(1):1-10. (PMID: 11169432)
Hum Mol Genet. 2010 Jan 1;19(1):111-21. (PMID: 19819884)
J Allergy Clin Immunol. 2006 Jun;117(6):1277-84. (PMID: 16750987)
J Immunol. 1981 Aug;127(2):788-94. (PMID: 7019332)
Nature. 2007 Jul 26;448(7152):470-3. (PMID: 17611496)
J Biol Chem. 2022 Feb;298(2):101517. (PMID: 34942147)
J Lipid Res. 2009 Apr;50 Suppl:S423-8. (PMID: 19095631)
Nat Commun. 2013;4:2479. (PMID: 24056518)
Immunol Invest. 2019 Apr;48(3):303-320. (PMID: 30335529)
Nat Med. 2012 May 04;18(5):693-704. (PMID: 22561833)
Nat Rev Mol Cell Biol. 2018 Mar;19(3):175-191. (PMID: 29165427)
Elife. 2019 Dec 27;8:. (PMID: 31880535)
Nat Prod Rep. 2018 Sep 19;35(9):921-954. (PMID: 29863195)
EMBO Rep. 2023 Jan 9;24(1):e54689. (PMID: 36408842)
Allergy. 2016 Jul;71(7):918-30. (PMID: 26969910)
Nat Immunol. 2016 Jul;17(7):878-87. (PMID: 27135604)
Front Immunol. 2021 Feb 11;11:591975. (PMID: 33643282)
Front Immunol. 2017 May 22;8:587. (PMID: 28588581)
Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3728-33. (PMID: 25775599)
Immun Inflamm Dis. 2021 Dec;9(4):1394-1405. (PMID: 34288557)
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16648-53. (PMID: 23011799)

37341-29-0 (Immunoglobulin E)
0 (Membrane Proteins)
0 (ORMDL1 protein, mouse)
0 (ORMDL3 protein, mouse)
0 (Sphingolipids)

Date Created: 20230614 Date Completed: 20240219 Latest Revision: 20240219

20250114

PMC10267218

10.1038/s41598-023-36344-5

37316542