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

0574786 - ÚMG 2024 RIV US eng J - Journal Article
Demková, Lívia - Bugajev, Viktor - Utekal, Pavol - Kuchař, L. - Schuster, Bjorn - Dráber, Petr - Hálová, Ivana
Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation.
Scientific Reports. Roč. 13, č. 1 (2023), č. článku 9615. ISSN 2045-2322. E-ISSN 2045-2322
R&D Projects: GA ČR GA18-18521S; GA ČR GA20-16481S; GA ČR(CZ) GA23-07736S; GA MŠMT(CZ) LM2018126; GA MŠMT(CZ) LM2015040; GA MŠMT(CZ) EF18_046/0016045
Institutional support: RVO:68378050
Keywords : ORMDL proteins * mast cell activation * sphingolipid metabolism
OECD category: Cell biology
Impact factor: 4.6, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s41598-023-36344-5

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.
Permanent Link: https://hdl.handle.net/11104/0346256