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ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

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) 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)_RID
Number 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	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

Number of the records: 1