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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Lung Injury / complications*
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Acute Lung Injury / pathology
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Animals
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Aorta, Abdominal / cytology
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Aorta, Abdominal / pathology
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Aortic Aneurysm, Abdominal / etiology
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Aortic Aneurysm, Abdominal / pathology*
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Aortic Aneurysm, Abdominal / prevention & control
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Cells, Cultured
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Disease Models, Animal
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Dynamins / antagonists & inhibitors
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Dynamins / metabolism
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HMGB1 Protein / metabolism*
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Humans
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Macrophages / cytology
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Macrophages / metabolism*
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Matrix Metalloproteinase 12 / genetics
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Matrix Metalloproteinase 12 / metabolism
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Mice
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Mice, Knockout
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Mitochondrial Dynamics / drug effects
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Oxidative Stress / drug effects
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Phosphorylation
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Primary Cell Culture
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Proteolysis / drug effects
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Pulmonary Disease, Chronic Obstructive / complications
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Pulmonary Disease, Chronic Obstructive / pathology
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Retrospective Studies
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Up-Regulation
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Vascular Remodeling*
Substances
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HMGB1 Protein
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HMGB1 protein, human
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HMGB1 protein, mouse
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse
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Matrix Metalloproteinase 12
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matrix metallopeptidase 12, mouse
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Dnm1l protein, mouse
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Dynamins