Journal Article

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

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

2007

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adoptive Transfer / aneurysm / Aneurysms / Animals / Antibodies / Aorta / Aortic Aneurysm, Abdominal - chemically induced / Aortic Aneurysm, Abdominal - enzymology / Aortic Aneurysm, Abdominal - pathology / Biological Sciences / Cathepsin C - deficiency / Cathepsin C - metabolism / cathepsin G / chemokine CXCL2 / Chemokines, CXC - biosynthesis / cysteine proteinases / Dilatation / elastase / Elastic tissue / Gene Expression Regulation / Immunoglobulins / inflammation / Leukocytes / Male / Messenger RNA / Mice / Mice, Inbred C57BL / Mutation / neutralizing antibodies / Neutrophil infiltration / Neutrophil Infiltration - immunology / Neutrophils / Neutrophils - cytology / Neutrophils - enzymology / Pancreatic Elastase / Perfusion / Proteases / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Vascular diseases / Vein & artery diseases