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Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts
In this study we analyzed whether anti-β2-GPI antibodies from patients with APS induce the endothelial cell expression of Tissue Factor (TF) by a LRP6 signal transduction pathway involving lipid rafts. HUVEC were stimulated with affinity purified anti-β2-GPI antibodies. Both LRP6 and β-catenin phosp...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025633/ https://www.ncbi.nlm.nih.gov/pubmed/35455968 http://dx.doi.org/10.3390/cells11081288 |
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author | Riitano, Gloria Capozzi, Antonella Recalchi, Serena Caissutti, Daniela Longo, Agostina Mattei, Vincenzo Conti, Fabrizio Misasi, Roberta Garofalo, Tina Sorice, Maurizio Manganelli, Valeria |
author_facet | Riitano, Gloria Capozzi, Antonella Recalchi, Serena Caissutti, Daniela Longo, Agostina Mattei, Vincenzo Conti, Fabrizio Misasi, Roberta Garofalo, Tina Sorice, Maurizio Manganelli, Valeria |
author_sort | Riitano, Gloria |
collection | PubMed |
description | In this study we analyzed whether anti-β2-GPI antibodies from patients with APS induce the endothelial cell expression of Tissue Factor (TF) by a LRP6 signal transduction pathway involving lipid rafts. HUVEC were stimulated with affinity purified anti-β2-GPI antibodies. Both LRP6 and β-catenin phosphorylation, as well as TF expression, were evaluated by western blot. Results demonstrated that triggering with affinity purified anti-β2-GPI antibodies induced LRP6 phosphorylation with consequent β-catenin activation, leading to TF expression on the cell surface. Interestingly, the lipid rafts affecting agent methyl-β-cyclodextrin as well as the LRP6 inhibitor Dickkopf 1 (DKK1) partially reduced the anti-β2-GPI antibodies effect, indicating that the anti-β2-GPI effects on TF expression may depend on a signalling transduction pathway involving both lipid rafts and LRP6. An interaction between β2-GPI, LRP6 and PAR-2 within these microdomains was demonstrated by gradient fractionation and coimmunoprecipitation experiments. Thus, anti-β2-GPI antibodies react with their target antigen likely associated to LRP6 and PAR-2 within plasma membrane lipid rafts of the endothelial cell. Anti-β2-GPI binding triggers β-catenin phosphorylation, leading to a procoagulant phenotype characterized by TF expression. These findings deal with a novel signal transduction pathway which provides new insight in the APS pathogenesis, improving the knowledge of valuable therapeutic target(s). |
format | Online Article Text |
id | pubmed-9025633 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90256332022-04-23 Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts Riitano, Gloria Capozzi, Antonella Recalchi, Serena Caissutti, Daniela Longo, Agostina Mattei, Vincenzo Conti, Fabrizio Misasi, Roberta Garofalo, Tina Sorice, Maurizio Manganelli, Valeria Cells Article In this study we analyzed whether anti-β2-GPI antibodies from patients with APS induce the endothelial cell expression of Tissue Factor (TF) by a LRP6 signal transduction pathway involving lipid rafts. HUVEC were stimulated with affinity purified anti-β2-GPI antibodies. Both LRP6 and β-catenin phosphorylation, as well as TF expression, were evaluated by western blot. Results demonstrated that triggering with affinity purified anti-β2-GPI antibodies induced LRP6 phosphorylation with consequent β-catenin activation, leading to TF expression on the cell surface. Interestingly, the lipid rafts affecting agent methyl-β-cyclodextrin as well as the LRP6 inhibitor Dickkopf 1 (DKK1) partially reduced the anti-β2-GPI antibodies effect, indicating that the anti-β2-GPI effects on TF expression may depend on a signalling transduction pathway involving both lipid rafts and LRP6. An interaction between β2-GPI, LRP6 and PAR-2 within these microdomains was demonstrated by gradient fractionation and coimmunoprecipitation experiments. Thus, anti-β2-GPI antibodies react with their target antigen likely associated to LRP6 and PAR-2 within plasma membrane lipid rafts of the endothelial cell. Anti-β2-GPI binding triggers β-catenin phosphorylation, leading to a procoagulant phenotype characterized by TF expression. These findings deal with a novel signal transduction pathway which provides new insight in the APS pathogenesis, improving the knowledge of valuable therapeutic target(s). MDPI 2022-04-11 /pmc/articles/PMC9025633/ /pubmed/35455968 http://dx.doi.org/10.3390/cells11081288 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Riitano, Gloria Capozzi, Antonella Recalchi, Serena Caissutti, Daniela Longo, Agostina Mattei, Vincenzo Conti, Fabrizio Misasi, Roberta Garofalo, Tina Sorice, Maurizio Manganelli, Valeria Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title | Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title_full | Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title_fullStr | Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title_full_unstemmed | Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title_short | Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts |
title_sort | anti-β2-gpi antibodies induce endothelial cell expression of tissue factor by lrp6 signal transduction pathway involving lipid rafts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025633/ https://www.ncbi.nlm.nih.gov/pubmed/35455968 http://dx.doi.org/10.3390/cells11081288 |
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