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

Rida Al-Rifai, Marie Vandestienne, Jean-Rémi Lavillegrand, Tristan Mirault, Julie Cornebise, Johanne Poisson, Ludivine Laurans, Bruno Esposito, Chloé James, Olivier Mansier, Pierre Hirsch, Fabrizia Favale, Rayan Braik, Camille Knosp, Jose Vilar, Giuseppe Rizzo, Alma Zernecke, Antoine-Emmanuel Saliba, Alain Tedgui, Maxime Lacroix, Lionel Arrive, Ziad Mallat, Soraya Taleb, Marc Diedisheim, Clément Cochain, Pierre-Emmanuel Rautou and Hafid Ait-Oufella ()
Additional contact information
Rida Al-Rifai: Université Paris Cité, Inserm, PARCC, F-75015
Marie Vandestienne: Université Paris Cité, Inserm, PARCC, F-75015
Jean-Rémi Lavillegrand: Université Paris Cité, Inserm, PARCC, F-75015
Tristan Mirault: Université Paris Cité, Inserm, PARCC, F-75015
Julie Cornebise: Université Paris Cité, Inserm, PARCC, F-75015
Johanne Poisson: Université Paris Cité, Inserm, PARCC, F-75015
Ludivine Laurans: Université Paris Cité, Inserm, PARCC, F-75015
Bruno Esposito: Université Paris Cité, Inserm, PARCC, F-75015
Chloé James: Université de Bordeaux, UMR1034, Inserm, Biology of Cardiovascular Diseases, CHU de Bordeaux, Laboratoire d’Hématologie
Olivier Mansier: Université de Bordeaux, UMR1034, Inserm, Biology of Cardiovascular Diseases, CHU de Bordeaux, Laboratoire d’Hématologie
Pierre Hirsch: Hôpital Saint-Antoine, AP-HP
Fabrizia Favale: Hôpital Saint-Antoine, AP-HP
Rayan Braik: Université Paris Cité, Inserm, PARCC, F-75015
Camille Knosp: Université Paris Cité, Inserm, PARCC, F-75015
Jose Vilar: Université Paris Cité, Inserm, PARCC, F-75015
Giuseppe Rizzo: University Hospital Wuerzburg
Alma Zernecke: University Hospital Wuerzburg
Antoine-Emmanuel Saliba: Helmholtz-Center for Infection Research (HZI)
Alain Tedgui: Université Paris Cité, Inserm, PARCC, F-75015
Maxime Lacroix: Hôpital Saint-Antoine, AP-HP
Lionel Arrive: Hôpital Saint-Antoine, AP-HP
Ziad Mallat: Université Paris Cité, Inserm, PARCC, F-75015
Soraya Taleb: Université Paris Cité, Inserm, PARCC, F-75015
Marc Diedisheim: Hôpital Cochin
Clément Cochain: University Hospital Wuerzburg
Pierre-Emmanuel Rautou: Université Paris Cité, Inserm, PARCC, F-75015
Hafid Ait-Oufella: Université Paris Cité, Inserm, PARCC, F-75015

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34469-1

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