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, José Vilar, Giuseppe Rizzo, Alma Zernecke, Antoine‐Emmanuel Saliba, Alain Tedgui, Maxime Lacroix, Lionel Arrivé, Ziad Mallat, Soraya Taleb, Marc Diedisheim, Clément Cochain, Pierre‐Emmanuel Rautou, Hafid Ait‐Oufella
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.