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Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease
Major Histocompatibility Complex (MHC) molecules have been proposed to play a role in Sickle Cell Disease (SCD) pathophysiology. Endothelial cells express MHC molecules following exposure to cytokines. SCD is characterized, in part, by vascular endothelial cell activation, increased oxidative stress...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011151/ https://www.ncbi.nlm.nih.gov/pubmed/36926339 http://dx.doi.org/10.3389/fimmu.2023.1124269 |
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author | Inostroza-Nieves, Yaritza Rivera, Alicia Romero, José R. |
author_facet | Inostroza-Nieves, Yaritza Rivera, Alicia Romero, José R. |
author_sort | Inostroza-Nieves, Yaritza |
collection | PubMed |
description | Major Histocompatibility Complex (MHC) molecules have been proposed to play a role in Sickle Cell Disease (SCD) pathophysiology. Endothelial cells express MHC molecules following exposure to cytokines. SCD is characterized, in part, by vascular endothelial cell activation, increased oxidative stress, sickle cell adhesion, and excess levels of endothelin-1 (ET-1) contributing to vaso-occlusive crises. ET-1 activates endothelial cells, induces oxidative stress and inflammation, and alters erythrocyte volume homeostasis. However, the role of ET-1 on MHC regulation in SCD is unclear. We first studied two sickle transgenic knockout mouse models of moderate to severe disease phenotype, βS-Antilles and Berkeley (BERK) mice. We observed significant increases in H2-Aa mRNA levels in spleens, lungs, and kidneys from transgenic sickle mice when compared to transgenic knockout mice expressing human hemoglobin A (HbA). Mice treated for 14 days with ET-1 receptor antagonists significantly reduced H2-Aa mRNA levels. We characterized the effect of ET-1 on MHC class II expression in the human endothelial cell line EA.hy926. We observed dose-dependent increases in the expression of MHC class II (HLA-DRA) and MHC transcription factor (CIITA) that were significantly blocked by treatment with BQ788, a selective blocker of ET-1 type B receptors. Chromatin immunoprecipitation studies in EA.hy926 cells showed that ET-1 increased Histone H3 acetylation of the HLA-DRA promoter, an event blocked by BQ788 treatment. These results implicate ET-1 as a novel regulator of MHC class II molecules and suggest that ET-1 receptor blockade represents a promising therapeutic approach to regulate both immune and vascular responses in SCD. |
format | Online Article Text |
id | pubmed-10011151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100111512023-03-15 Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease Inostroza-Nieves, Yaritza Rivera, Alicia Romero, José R. Front Immunol Immunology Major Histocompatibility Complex (MHC) molecules have been proposed to play a role in Sickle Cell Disease (SCD) pathophysiology. Endothelial cells express MHC molecules following exposure to cytokines. SCD is characterized, in part, by vascular endothelial cell activation, increased oxidative stress, sickle cell adhesion, and excess levels of endothelin-1 (ET-1) contributing to vaso-occlusive crises. ET-1 activates endothelial cells, induces oxidative stress and inflammation, and alters erythrocyte volume homeostasis. However, the role of ET-1 on MHC regulation in SCD is unclear. We first studied two sickle transgenic knockout mouse models of moderate to severe disease phenotype, βS-Antilles and Berkeley (BERK) mice. We observed significant increases in H2-Aa mRNA levels in spleens, lungs, and kidneys from transgenic sickle mice when compared to transgenic knockout mice expressing human hemoglobin A (HbA). Mice treated for 14 days with ET-1 receptor antagonists significantly reduced H2-Aa mRNA levels. We characterized the effect of ET-1 on MHC class II expression in the human endothelial cell line EA.hy926. We observed dose-dependent increases in the expression of MHC class II (HLA-DRA) and MHC transcription factor (CIITA) that were significantly blocked by treatment with BQ788, a selective blocker of ET-1 type B receptors. Chromatin immunoprecipitation studies in EA.hy926 cells showed that ET-1 increased Histone H3 acetylation of the HLA-DRA promoter, an event blocked by BQ788 treatment. These results implicate ET-1 as a novel regulator of MHC class II molecules and suggest that ET-1 receptor blockade represents a promising therapeutic approach to regulate both immune and vascular responses in SCD. Frontiers Media S.A. 2023-02-28 /pmc/articles/PMC10011151/ /pubmed/36926339 http://dx.doi.org/10.3389/fimmu.2023.1124269 Text en Copyright © 2023 Inostroza-Nieves, Rivera and Romero https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Inostroza-Nieves, Yaritza Rivera, Alicia Romero, José R. Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title | Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title_full | Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title_fullStr | Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title_full_unstemmed | Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title_short | Blockade of endothelin-1 receptor B regulates molecules of the major histocompatibility complex in sickle cell disease |
title_sort | blockade of endothelin-1 receptor b regulates molecules of the major histocompatibility complex in sickle cell disease |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011151/ https://www.ncbi.nlm.nih.gov/pubmed/36926339 http://dx.doi.org/10.3389/fimmu.2023.1124269 |
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