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Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages

Abstract : Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.
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https://www.hal.inserm.fr/inserm-02962465
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Submitted on : Friday, October 9, 2020 - 11:28:45 AM
Last modification on : Wednesday, June 2, 2021 - 4:26:06 PM
Long-term archiving on: : Sunday, January 10, 2021 - 6:28:52 PM

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Ludovic Boytard, Tarik Hadi, Michele Silvestro, Hengdong Qu, Andrew Kumpfbeck, et al.. Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.4311. ⟨10.1038/s41467-020-18088-2⟩. ⟨inserm-02962465⟩

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