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ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling
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SYSNO ASEP 0544782 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling Author(s) Bugajev, Viktor (UMG-J) RID
Hálová, Ivana (UMG-J) RID, ORCID
Demková, Lívia (UMG-J) ORCID
Černohouzová, Sára (UMG-J)
Vávrová, Petra (UMG-J)
Mrkáček, Michal (UMG-J)
Utekal, Pavol (UMG-J)
Dráberová, Lubica (UMG-J) RID
Kuchař, L. (CZ)
Schuster, Bjorn (UMG-J)
Dráber, Petr (UMG-J) RIDNumber of authors 11 Article number 591975 Source Title Frontiers in Immunology. - : Frontiers Media - ISSN 1664-3224
Roč. 11, February (2021)Number of pages 17 s. Publication form Online - E Language eng - English Country CH - Switzerland Keywords mast cells ; passive systemic anaphylaxis ; Fcϵ ; ri ; sphingolipids ; ORMDL family ; sphingosine-1-phosphate ; passive cutaneous anaphylactic reaction Subject RIV EB - Genetics ; Molecular Biology OECD category Immunology R&D Projects GA17-20915S GA ČR - Czech Science Foundation (CSF) GA18-18521S GA ČR - Czech Science Foundation (CSF) GA20-16481S GA ČR - Czech Science Foundation (CSF) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000621390600001 DOI https://doi.org/10.3389/fimmu.2020.591975 Annotation The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis of sphingolipids in mammalian cells is inhibited by the family of three ORMDL proteins (ORMDL1, 2, and 3). However, the cell and tissue-specific functions of ORMDL proteins in mast cell signaling are poorly understood. This study aimed to determine cross-talk of ORMDL2 and ORMDL3 proteins in IgE-mediated responses. To this end, we prepared mice with whole-body knockout (KO) of Ormdl2 and/or Ormdl3 genes and studied their role in mast cell-dependent activation events in vitro and in vivo. We found that the absence of ORMDL3 in bone marrow-derived mast cells (BMMCs) increased the levels of cellular sphingolipids. Such an increase was further raised by simultaneous ORMDL2 deficiency, which alone had no effect on sphingolipid levels. Cells with double ORMDL2 and ORMDL3 KO exhibited increased intracellular levels of sphingosine-1-phosphate (S1P). Furthermore, we found that concurrent ORMDL2 and ORMDL3 deficiency increased I kappa B-alpha phosphorylation, degranulation, and production of IL-4, IL-6, and TNF-alpha cytokines in antigen-activated mast cells. Interestingly, the chemotaxis towards antigen was increased in all mutant cell types analyzed. Experiments in vivo showed that passive cutaneous anaphylaxis (PCA), which is initiated by mast cell activation, was increased only in ORMDL2,3 double KO mice, supporting our in vitro observations with mast cells. On the other hand, ORMDL3 KO and ORMDL2,3 double KO mice showed faster recovery from passive systemic anaphylaxis, which could be mediated by increased levels of blood S1P presented in such mice. Our findings demonstrate that Ormdl2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2022 Electronic address https://www.frontiersin.org/articles/10.3389/fimmu.2020.591975/full
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