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Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice
The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3(DNGR1-KO) mice develop pulmonary hypertension (PH) symptoms. These mice harbor...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916474/ https://www.ncbi.nlm.nih.gov/pubmed/33578743 http://dx.doi.org/10.3390/ijms22041756 |
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author | van Uden, Denise Koudstaal, Thomas van Hulst, Jennifer A. C. Bergen, Ingrid M. Gootjes, Chelsea Morrell, Nicholas W. van Loo, Geert von der Thüsen, Jan H. van den Bosch, Thierry P. P. Ghigna, Maria-Rosa Perros, Frédéric Montani, David Kool, Mirjam Boomars, Karin A. Hendriks, Rudi W. |
author_facet | van Uden, Denise Koudstaal, Thomas van Hulst, Jennifer A. C. Bergen, Ingrid M. Gootjes, Chelsea Morrell, Nicholas W. van Loo, Geert von der Thüsen, Jan H. van den Bosch, Thierry P. P. Ghigna, Maria-Rosa Perros, Frédéric Montani, David Kool, Mirjam Boomars, Karin A. Hendriks, Rudi W. |
author_sort | van Uden, Denise |
collection | PubMed |
description | The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3(DNGR1-KO) mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3(DNGR1-KO) mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3(DNGR1-KO) mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3(DNGR1-KO) mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene. |
format | Online Article Text |
id | pubmed-7916474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79164742021-03-01 Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice van Uden, Denise Koudstaal, Thomas van Hulst, Jennifer A. C. Bergen, Ingrid M. Gootjes, Chelsea Morrell, Nicholas W. van Loo, Geert von der Thüsen, Jan H. van den Bosch, Thierry P. P. Ghigna, Maria-Rosa Perros, Frédéric Montani, David Kool, Mirjam Boomars, Karin A. Hendriks, Rudi W. Int J Mol Sci Article The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3(DNGR1-KO) mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3(DNGR1-KO) mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3(DNGR1-KO) mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3(DNGR1-KO) mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene. MDPI 2021-02-10 /pmc/articles/PMC7916474/ /pubmed/33578743 http://dx.doi.org/10.3390/ijms22041756 Text en © 2021 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/). |
spellingShingle | Article van Uden, Denise Koudstaal, Thomas van Hulst, Jennifer A. C. Bergen, Ingrid M. Gootjes, Chelsea Morrell, Nicholas W. van Loo, Geert von der Thüsen, Jan H. van den Bosch, Thierry P. P. Ghigna, Maria-Rosa Perros, Frédéric Montani, David Kool, Mirjam Boomars, Karin A. Hendriks, Rudi W. Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title | Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title_full | Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title_fullStr | Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title_full_unstemmed | Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title_short | Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice |
title_sort | central role of dendritic cells in pulmonary arterial hypertension in human and mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916474/ https://www.ncbi.nlm.nih.gov/pubmed/33578743 http://dx.doi.org/10.3390/ijms22041756 |
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