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3 results on '"Tatyana N. Sevastyanova"'

1. Titanium Nanoparticles Enhance Production and Suppress Stabilin-1-Mediated Clearance of GDF-15 in Human Primary Macrophages

Author

Lina S. Silva-Bermudez, Tatyana N. Sevastyanova, Christina Schmuttermaier, Carolina De La Torre, Leonie Schumacher, Harald Klüter, and Julia Kzhyshkowska

Subjects
titanium, nanoparticle, macrophage, endocytosis, scavenger receptor, growth factor, Immunologic diseases. Allergy, RC581-607
Abstract

Macrophages are key innate immune cells that mediate implant acceptance or rejection. Titanium implants degrade over time inside the body, which results in the release of implant wear-off particles. Titanium nanoparticles (TiNPs) favor pro-inflammatory macrophage polarization (M1) and lower tolerogenic activation (M2). GDF-15 regulates immune tolerance and fibrosis and is endocytosed by stabilin-1. How TiNPs affect the healing activities of macrophages and their release of circulating cytokines is an open question in regenerative medicine. In this study for the first time, we identified the transcriptional program induced and suppressed by TiNPs in human pro-inflammatory and healing macrophages. Microarray analysis revealed that TiNPs altered the expression of 5098 genes in M1 (IFN-γ-stimulated) and 4380 genes in M2 (IL-4–stimulated) macrophages. 1980 genes were differentially regulated in both M1 and M2. Affymetrix analysis, confirmed by RT-PCR, demonstrated that TiNPs upregulate expression of GDF-15 and suppress stabilin-1, scavenger receptor of GDF-15. TiNPs also significantly stimulated GDF-15 protein secretion in inflammatory and healing macrophages. Flow cytometry demonstrated, that scavenging activity of stabilin-1 was significantly suppressed by TiNPs. Confocal microscopy analysis showed that TiNPs impair internalization of stabilin-1 ligand acLDL and its transport to the endocytic pathway. Our data demonstrate that TiNPs have a dual effect on the GDF-15/stabilin-1 interaction in macrophage system, by increasing the production of GDF-15 and suppressing stabilin-1-mediated clearance function. In summary, this process can result in a significant increase of GDF-15 in the extracellular space and in circulation leading to unbalanced pro-fibrotic reactions and implant complications.

Published
2021
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2. Cooperative Signaling between Homodimers of Metabotropic Glutamate Receptors 1 and 5

Author

Tatyana N. Sevastyanova and Paul J. Kammermeier

Subjects
Male, Receptor, Metabotropic Glutamate 5, Glutamic Acid, Class C GPCR, Superior Cervical Ganglion, Biology, Receptors, Metabotropic Glutamate, Allosteric Regulation, mental disorders, Animals, Rats, Wistar, Long-term depression, Neurons, Pharmacology, Metabotropic glutamate receptor 5, Metabotropic glutamate receptor 7, Metabotropic glutamate receptor 6, Articles, Rats, Cell biology, nervous system, Biochemistry, Metabotropic glutamate receptor, Molecular Medicine, Metabotropic glutamate receptor 1, Calcium, Metabotropic glutamate receptor 2, Signal Transduction
Abstract

Metabotropic glutamate receptors (mGluRs) function as dimers. Recent work suggests that mGluR1 and mGluR5 may physically interact, but the nature and functional consequences of this relationship have not been addressed. In this study, the functional and pharmacological consequences of this interaction were investigated. Using heterologous expression of mGluR cDNA in rat sympathetic neurons from the superior cervical ganglion and inhibition of the native calcium currents as an assay for receptor activation, a functional interdependence between mGluR1 and mGluR5 was demonstrated. In neurons coexpressing these receptors, combining a selective mGluR1 competitive antagonist with either an mGluR1- or mGluR5-selective negative allosteric modulator (NAM) BAY36-7620 [(3aS,6aS)-hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one] or MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], respectively, strongly occluded signaling by both receptors to an approximately equal degree. By contrast, in cells coexpressing mGluR1 and mGluR2, combining the same mGluR1 competitive inhibitor with an mGluR1 or mGluR2 NAM yielded partial and full inhibition of the response, respectively, as expected for independently acting receptors. In neurons expressing mGluR1 and mGluR5, the selective NAMs each strongly inhibited the response to glutamate, suggesting that these receptors do not interact as heterodimers, which would not be inhibited by selective NAMs. Finally, evidence for a similar mGluR1/mGluR5 functional dependence is shown in medium spiny striatal neurons. Together, these data demonstrate cooperative signaling between mGluR1 and mGluR5 in a manner inconsistent with heterodimerization, and thus suggest an interaction between homodimers.

Published
2014
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