Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages.

Abstract

Macrophage class A1 scavenger receptor (SR-A1) is a pattern recognition receptor with an anti-inflammatory feature in cardiovascular diseases. However, its role in acute aortic dissection (AD) is not known yet. Using an aortic dissection model in SR-A1-deficient mice and their wild type littermates, we found that SR-A1 deficiency aggravated beta-aminopropionitrile monofumarate induced thoracic aortic dilation, false lumen formation, extracellular matrix degradation, vascular inflammation and accumulation of apoptotic cells. These pathological changes were associated with an impaired macrophage efferocytosis mediated by tyrosine-protein kinase receptor Tyro3 in vitro and in vivo. SR-A1 could directly interact with Tyro3 and was required for Tyro3 phosphorylation to activate its downstream PI3K/Akt signaling pathway. Importantly, co-culture of SR-A1-/- macrophages with apoptotic Jurkat cells resulted in less devoured apoptotic cells accompanied by swelling mitochondria and damaged ATP generation, following poor IL-10 and robust TNF-α production. Deficiency of SR-A1 did not influence phagolysosome formation during the efferocytosis. Lentiviral overexpression of Tyro3 in SR-A1-/- macrophages induced restorative phagocytosis in vitro. Administration of Tyro3 agonist protein S could restore SR-A1-/- macrophages phagocytosis in vitro and in vivo. These findings suggest that SR-A1-Tyro3 axis in macrophages mitigate AD damage by promoting efferocytosis and inhibiting inflammation.

• Authors: Zhi Zhang, Yunlong Jiang, Zhongqiu Zhou, Jianan Huang, Shichao Chen, Wenying Zhou, Qing Yang, Hui Bai, Hanwen Zhang, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qi Chen
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 168 Pg. 392-403 (10 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 31381873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• MSR1 protein, human
• Msr1 protein, mouse
• Scavenger Receptors, Class A
• beta-aminopropionitrile fumarate
• Aminopropionitrile
• Staurosporine

Topics

• Aminopropionitrile (analogs & derivatives, pharmacology)
• Aortic Dissection
• Animals
• Apoptosis
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (drug effects)
• HEK293 Cells
• Humans
• Inflammation
• Jurkat Cells
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Scavenger Receptors, Class A (genetics, metabolism)
• Staurosporine (pharmacology)