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

Al-Rifai R, Vandestienne M, Lavillegrand JR, Mirault T, Cornebise J, Poisson J, Laurans L, Esposito B, James C, Mansier O, Hirsch P, Favale F, Braik R, Knosp C, Vilar J, Rizzo G, Zernecke A, Saliba AE, Tedgui A, Lacroix M, Arrive L, Mallat Z, Taleb S, Diedisheim M, Cochain C, Rautou PE, Ait-Oufella H (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 13

Article Number: 6592

Journal Issue: 1

DOI: 10.1038/s41467-022-34469-1

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.

Involved external institutions

Université de Paris FR France (FR) Institut national de physique nucléaire et de physique des particules (IN2P3) FR France (FR) Hôpital Saint-Antoine FR France (FR) Universitätsklinikum Würzburg DE Germany (DE) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE)

How to cite

APA:

Al-Rifai, R., Vandestienne, M., Lavillegrand, J.-R., Mirault, T., Cornebise, J., Poisson, J.,... Ait-Oufella, H. (2022). JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-34469-1

MLA:

Al-Rifai, Rida, et al. "JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm." Nature Communications 13.1 (2022).

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