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

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.

• Authors: Monica B Pagano, Michel A Bartoli, Terri L Ennis, Dongli Mao, Pamela M Simmons, Robert W Thompson, Christine T N Pham
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 8 Pg. 2855-60 (Feb 20 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17301245 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chemokines, CXC
• RNA, Messenger
• Cathepsin C
• Pancreatic Elastase

Topics

• Adoptive Transfer
• Animals
• Aortic Aneurysm, Abdominal (chemically induced, enzymology, pathology)
• Cathepsin C (deficiency, metabolism)
• Chemokines, CXC (biosynthesis)
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration (immunology)
• Neutrophils (cytology, enzymology)
• Pancreatic Elastase
• RNA, Messenger (genetics, metabolism)