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JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk facto...

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Autores principales: Al-Rifai, Rida, Vandestienne, Marie, Lavillegrand, Jean-Rémi, Mirault, Tristan, Cornebise, Julie, Poisson, Johanne, Laurans, Ludivine, Esposito, Bruno, James, Chloé, Mansier, Olivier, Hirsch, Pierre, Favale, Fabrizia, Braik, Rayan, Knosp, Camille, Vilar, Jose, Rizzo, Giuseppe, Zernecke, Alma, Saliba, Antoine-Emmanuel, Tedgui, Alain, Lacroix, Maxime, Arrive, Lionel, Mallat, Ziad, Taleb, Soraya, Diedisheim, Marc, Cochain, Clément, Rautou, Pierre-Emmanuel, Ait-Oufella, Hafid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633755/
https://www.ncbi.nlm.nih.gov/pubmed/36329047
http://dx.doi.org/10.1038/s41467-022-34469-1
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author Al-Rifai, Rida
Vandestienne, Marie
Lavillegrand, Jean-Rémi
Mirault, Tristan
Cornebise, Julie
Poisson, Johanne
Laurans, Ludivine
Esposito, Bruno
James, Chloé
Mansier, Olivier
Hirsch, Pierre
Favale, Fabrizia
Braik, Rayan
Knosp, Camille
Vilar, Jose
Rizzo, Giuseppe
Zernecke, Alma
Saliba, Antoine-Emmanuel
Tedgui, Alain
Lacroix, Maxime
Arrive, Lionel
Mallat, Ziad
Taleb, Soraya
Diedisheim, Marc
Cochain, Clément
Rautou, Pierre-Emmanuel
Ait-Oufella, Hafid
author_facet Al-Rifai, Rida
Vandestienne, Marie
Lavillegrand, Jean-Rémi
Mirault, Tristan
Cornebise, Julie
Poisson, Johanne
Laurans, Ludivine
Esposito, Bruno
James, Chloé
Mansier, Olivier
Hirsch, Pierre
Favale, Fabrizia
Braik, Rayan
Knosp, Camille
Vilar, Jose
Rizzo, Giuseppe
Zernecke, Alma
Saliba, Antoine-Emmanuel
Tedgui, Alain
Lacroix, Maxime
Arrive, Lionel
Mallat, Ziad
Taleb, Soraya
Diedisheim, Marc
Cochain, Clément
Rautou, Pierre-Emmanuel
Ait-Oufella, Hafid
author_sort Al-Rifai, Rida
collection PubMed
description JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
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spelling pubmed-96337552022-11-05 JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm Al-Rifai, Rida Vandestienne, Marie Lavillegrand, Jean-Rémi Mirault, Tristan Cornebise, Julie Poisson, Johanne Laurans, Ludivine Esposito, Bruno James, Chloé Mansier, Olivier Hirsch, Pierre Favale, Fabrizia Braik, Rayan Knosp, Camille Vilar, Jose Rizzo, Giuseppe Zernecke, Alma Saliba, Antoine-Emmanuel Tedgui, Alain Lacroix, Maxime Arrive, Lionel Mallat, Ziad Taleb, Soraya Diedisheim, Marc Cochain, Clément Rautou, Pierre-Emmanuel Ait-Oufella, Hafid Nat Commun Article JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm. Nature Publishing Group UK 2022-11-03 /pmc/articles/PMC9633755/ /pubmed/36329047 http://dx.doi.org/10.1038/s41467-022-34469-1 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Al-Rifai, Rida
Vandestienne, Marie
Lavillegrand, Jean-Rémi
Mirault, Tristan
Cornebise, Julie
Poisson, Johanne
Laurans, Ludivine
Esposito, Bruno
James, Chloé
Mansier, Olivier
Hirsch, Pierre
Favale, Fabrizia
Braik, Rayan
Knosp, Camille
Vilar, Jose
Rizzo, Giuseppe
Zernecke, Alma
Saliba, Antoine-Emmanuel
Tedgui, Alain
Lacroix, Maxime
Arrive, Lionel
Mallat, Ziad
Taleb, Soraya
Diedisheim, Marc
Cochain, Clément
Rautou, Pierre-Emmanuel
Ait-Oufella, Hafid
JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title_full JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title_fullStr JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title_full_unstemmed JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title_short JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
title_sort jak2v617f mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633755/
https://www.ncbi.nlm.nih.gov/pubmed/36329047
http://dx.doi.org/10.1038/s41467-022-34469-1
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