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. |
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| Authors: | Al-Rifai R; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Vandestienne M; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Lavillegrand JR; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Mirault T; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Service de médecine vasculaire, Hopital Européen G. Pompidou, Paris, France.; Cornebise J; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Poisson J; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Service de gériatrie, Hopital Européen G. Pompidou, Paris, France.; Centre de recherche sur l'inflammation, Inserm, Paris, France.; Laurans L; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Esposito B; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; James C; Université de Bordeaux, UMR1034, Inserm, Biology of Cardiovascular Diseases, CHU de Bordeaux, Laboratoire d'Hématologie, Pessac, France.; Mansier O; Université de Bordeaux, UMR1034, Inserm, Biology of Cardiovascular Diseases, CHU de Bordeaux, Laboratoire d'Hématologie, Pessac, France.; Hirsch P; Laboratoire d'Hématologie, Hôpital Saint-Antoine, AP-HP, Paris, France.; Favale F; Laboratoire d'Hématologie, Hôpital Saint-Antoine, AP-HP, Paris, France.; Braik R; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Knosp C; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Vilar J; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Rizzo G; Institute of Experimental Biomedicine, University Hospital Wuerzburg, Würzburg, Germany.; Zernecke A; Institute of Experimental Biomedicine, University Hospital Wuerzburg, Würzburg, Germany.; Saliba AE; Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany.; Tedgui A; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Lacroix M; Service de radiologie, Hôpital Saint-Antoine, AP-HP, Paris, France.; Arrive L; Service de radiologie, Hôpital Saint-Antoine, AP-HP, Paris, France.; Mallat Z; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Taleb S; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Diedisheim M; GlandOmics, 41700 Cheverny, & Department of Diabetology, AP-HP, Hôpital Cochin, Paris, France.; Cochain C; Institute of Experimental Biomedicine, University Hospital Wuerzburg, Würzburg, Germany.; Rautou PE; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France.; Centre de recherche sur l'inflammation, Inserm, Paris, France.; AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France.; Ait-Oufella H; Université Paris Cité, Inserm, PARCC, F-75015, Paris, France. hafid.aitoufella@inserm.fr.; Medical Intensive Care Unit, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France. hafid.aitoufella@inserm.fr. |
| Source: | Nature communications [Nat Commun] 2022 Nov 03; Vol. 13 (1), pp. 6592. Date of Electronic Publication: 2022 Nov 03. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Aortic Dissection*/pathology ; Aortic Aneurysm*/genetics ; Aortic Aneurysm*/complications; Macrophages/pathology ; Mice ; Animals ; Phenotype ; Mutation |
| 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.; (© 2022. The Author(s).) |
| Comments: | Erratum in: Nat Commun. 2022 Dec 23;13(1):7921. doi: 10.1038/s41467-022-35645-z.. (PMID: 36564399) |
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| Grant Information: | CH/10/001/27642 United Kingdom BHF_ British Heart Foundation |
| Entry Date(s): | Date Created: 20221104 Date Completed: 20221107 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9633755 |
| DOI: | 10.1038/s41467-022-34469-1 |
| PMID: | 36329047 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't