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Ceramide imbalance and impaired TLR4-Mediated autophagy in BMDM of an ORMDL3-overexpressing mouse model

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dc.contributor.author Kiefer, Kerstin, 1986-
dc.contributor.author Casas, Josefina
dc.contributor.author García López, Roberto, 1991-
dc.contributor.author Vicente García, Rubén, 1978-
dc.date.accessioned 2019-07-04T07:00:28Z
dc.date.available 2019-07-04T07:00:28Z
dc.date.issued 2019
dc.identifier.citation Kiefer K, Casas J, García-López R, Vicente R. Ceramide imbalance and impaired TLR4-Mediated autophagy in BMDM of an ORMDL3-overexpressing mouse model. Int J Mol Sci. 2019;20(6):1391. DOI: 10.3390/ijms20061391
dc.identifier.issn 1422-0067
dc.identifier.uri http://hdl.handle.net/10230/41928
dc.description.abstract Increased orosomucoid-like 3 (ORMDL3) expression levels, due to single nucleotide polymorphisms (SNPs), have been associated with several inflammatory diseases, including asthma and inflammatory bowel diseases. ORMDL proteins inhibit serine palmitoyltransferase (SPT), the first rate-limiting enzyme in de novo sphingolipid synthesis and alter cellular calcium homeostasis. Both processes are essential for immune response. The present study addresses ORMDL3 protein involvement in macrophage physiology using an overexpressing knock-in mouse model. Ceramide content was notably different in the bone-marrow-derived macrophages (BMDM) from the transgenic mouse model compared with the wild type (WT) macrophages. Our data revealed an alteration of de novo production of sphinganine upon BMDM activation in the transgenic mouse. Gene-expression analysis showed that alteration in ORMDL3 expression levels did not affect activation or macrophage polarization. Nevertheless, we studied phagocytosis and autophagy-crucial processes that are dependent on lipid membrane composition. Phagocytosis in transgenic macrophages was not affected by ORMDL3 overexpression, but we did find a reduction in toll-like receptor 4 (TLR-4)-mediated autophagy. Both genetic and functional studies have pointed to autophagy as an essential pathway involved in inflammation. We believe that our work provides new insights into the functional link between ORMDL3 expression and inflammatory diseases.
dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2010-16725, SAF2014-52228-R, and BES-2011-043839), Fondo de Investigación Sanitaria (Red HERACLES RD12/0042/0014), Unidad de Excelencia María de Maeztu, funded by the MINECO (MDM-2014-0370), and Fundació la Marató de TV3 (20134030).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher MDPI
dc.relation.ispartof International Journal of Molecular Sciences. 2019;20(6):1391
dc.rights © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Ceramide imbalance and impaired TLR4-Mediated autophagy in BMDM of an ORMDL3-overexpressing mouse model
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3390/ijms20061391
dc.subject.keyword ORMDL3
dc.subject.keyword Asthma
dc.subject.keyword Autophagy
dc.subject.keyword Ceramides
dc.subject.keyword Macrophages
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-16725
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BES-2011-043839
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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