Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms.
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.
Pagano
Monica B
MB
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63124, USA.
Bartoli
Michel A
MA
Ennis
Terri L
TL
Mao
Dongli
D
Simmons
Pamela M
PM
Thompson
Robert W
RW
Pham
Christine T N
CT
D019264:Adoptive Transfer; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D020789:Cathepsin C / Q000172:deficiency / Q000378:metabolism*; D019743:Chemokines, CXC / Q000096:biosynthesis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D010196:Pancreatic Elastase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D019743:Chemokines, CXC; D012333:RNA, Messenger; D020789:Cathepsin C; D010196:Pancreatic Elastase