Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells

Tarik Hadi, Ludovic Boytard, Michele Silvestro, Dornazsadat Alebrahim, Samson Jacob, Jordyn Feinstein, Krista Barone, Wes Spiro, Susan Hutchison, Russell Simon, Debra Rateri, Florence Pinet, David Fenyo, Mark Adelman, Kathryn J. Moore, Holger K. Eltzschig, Alan Daugherty and Bhama Ramkhelawon ()
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Tarik Hadi: New York University Medical Center
Ludovic Boytard: New York University Medical Center
Michele Silvestro: New York University Medical Center
Dornazsadat Alebrahim: New York University Medical Center
Samson Jacob: New York University School of Medicine
Jordyn Feinstein: New York University Medical Center
Krista Barone: New York University Medical Center
Wes Spiro: New York University School of Medicine
Susan Hutchison: New York University School of Medicine
Russell Simon: New York University Medical Center
Debra Rateri: University of Kentucky
Florence Pinet: University of Lille, Inserm U1167, Institut Pasteur de Lille
David Fenyo: New York University School of Medicine
Mark Adelman: New York University Medical Center
Kathryn J. Moore: New York University School of Medicine
Holger K. Eltzschig: University of Texas Health Science Center at Houston
Alan Daugherty: University of Kentucky
Bhama Ramkhelawon: New York University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.

Date: 2018
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DOI: 10.1038/s41467-018-07495-1

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