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Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation
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SYSNO ASEP 0574786 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation Author(s) Demková, Lívia (UMG-J)
Bugajev, Viktor (UMG-J) RID
Utekal, Pavol (UMG-J)
Kuchař, L. (CZ)
Schuster, Bjorn (UMG-J)
Dráber, Petr (UMG-J) RID
Hálová, Ivana (UMG-J) RID, ORCIDNumber of authors 7 Article number 9615 Source Title Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 13, č. 1 (2023)Number of pages 15 s. Language eng - English Country US - United States Keywords ORMDL proteins ; mast cell activation ; sphingolipid metabolism OECD category Cell biology R&D Projects GA18-18521S GA ČR - Czech Science Foundation (CSF) GA20-16481S GA ČR - Czech Science Foundation (CSF) GA23-07736S GA ČR - Czech Science Foundation (CSF) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015040 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0016045 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 001010888200038 EID SCOPUS 85161942876 DOI 10.1038/s41598-023-36344-5 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2024 Electronic address https://www.nature.com/articles/s41598-023-36344-5
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