Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation.
We previously established that neutrophil-derived dipeptidyl peptidase I (DPPI) is essential for experimental abdominal aortic aneurysm (AAA) development. Because DPPI activates several neutrophil serine proteases, it remains to be determined whether the AAA-promoting effect of DPPI is mediated by neutrophil serine proteases.



Using an elastase-induced AAA model, we demonstrate that the absence of 2 neutrophil serine proteases, neutrophil elastase and proteinase-3, recapitulates the AAA-resistant phenotype of DPPI-deficient mice. DPPI and neutrophil serine proteases direct the in vitro and in vivo release of extracellular structures termed neutrophil extracellular traps (NETs). Administration of DNase1, which dismantles NETs, suppresses elastase-induced AAA in wild-type animals and in DPPI-deficient mice reconstituted with wild-type neutrophils. NETs also contain the cathelicidin-related antimicrobial peptide that complexes with self-DNA in recruiting plasmacytoid dendritic cells (pDCs), inducing type I interferons (IFNs) and promoting AAA in DPPI-deficient mice. Conversely, depletion of pDCs or blockade of type I IFNs suppresses experimental AAA. Moreover, we find an abundance of human cathelicidin peptide, a 37 amino acid sequence starting with 2 leucines and the human orthologue of cathelicidin-related antimicrobial peptide, in the vicinity of pDCs in human AAA tissues. Increased type I IFN mRNA expression is observed in human AAA tissues and circulating IFN-α is detected in ≈50% of the AAA sera examined.



These results suggest that neutrophil protease-mediated NET release contributes to elastase-induced AAA through pDC activation and type I IFN production. These findings increase our understanding of the pathways underlying AAA inflammatory responses and suggest that limiting NET, pDC, and type I IFN activities may suppress aneurysm progression.
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Huimin
H
Yan
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Hui-Fang
HF
Zhou
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Antonina
A
Akk
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Ying
Y
Hu
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Luke E
LE
Springer
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Terri L
TL
Ennis
John Cochran VA Medical Center, Saint Louis, Missouri USA; the Department of Medicine, Division of Rheumatology and the Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
Christine T N
CTN
Pham
D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology*; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000201:enzymology*; D005838:Genotype; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053146:Myeloblastin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction
D007370:Interferon Type I; D020789:Cathepsin C; C533919:Ctsc protein, mouse; D019272:Leukocyte Elastase; D053146:Myeloblastin
aortic aneurysm, abdominal; dendritic cells; extracellular traps; interferon type I; neutrophil extracellular traps; plasmacytoid dendritic cells