Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Monica B. Pagano, Michel A. Bartoli, Terri L. Ennis, Dongli Mao, Pamela M. Simmons, Robert W. Thompson, Christine T.N. Pham

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease critical for the activation of granule-associated serine proteases, including neutrophil elastase, cathepsin G, and proteinase 3. DPPI and granule-associated serine proteases have been shown to play a key role in regulating neutrophil recruitment at sites of inflammation. It has recently been suggested that neutrophils and neutrophil-associated proteases may also be important in the development and progression of abdominal aortic aneurysms (AAAs), a common vascular disease associated with chronic inflammation and destructive remodeling of aortic wall connective tissue. Here we show that mice with a loss-of-function mutation in DPPI are resistant to the development of elastase-induced experimental AAAs. This is in part because of diminished recruitment of neutrophils to the elastase-injured aortic wall and impaired local production of CXC-chemokine ligand (CXCL) 2. Furthermore, adoptive transfer of wild-type neutrophils is sufficient to restore susceptibility to AAAs in DPPI-deficient mice, as well as aortic wall expression of CXCL2. In addition, in vivo blockade of CXCL2 by using neutralizing antibodies directed against its cognate receptor leads to a significant reduction in aortic dilatation. These findings suggest that DPPI and/or granule-associated serine proteases are necessary for neutrophil recruitment into the diseased aorta and that these proteases act to amplify vascular wall inflammation that leads to AAAs.

Original languageEnglish
Pages (from-to)2855-2860
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number8
DOIs
StatePublished - Feb 20 2007

Keywords

  • Cardiovascular
  • Inflammation
  • Innate immunity
  • Proteases

Fingerprint Dive into the research topics of 'Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms'. Together they form a unique fingerprint.

  • Cite this