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. cardiovascular ͉ inflammation ͉ innate immunity ͉ proteases

Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

“…This aortic diameter (AD) remained relatively stable up to day 7, after which there was rapid and significant increase in AD in WT mice (12,18). AAA is typically defined on day 14 as an increase in AD of 100% or greater than the diameter measured before elastase perfusion (12,18). We have previously shown that fB −/− mice are largely resistant to the development of AAA (increase in AD of 105 ± 4%) (12).…”

“…Properdin is in the plasma and also stored in neutrophil granules, where it is rapidly released during cell stimulation (15,19). To determine whether locally secreted properdin (derived from infiltrating neutrophils) can drive the AAA phenotype, we reconstituted fP −/o mice with purified bone marrow-derived neutrophils using a regimen that we had previously used to successfully restore AAA phenotype in the dipeptidyl peptidase I-deficient mice (18). WT neutrophils (1e7) were injected i.v.…”

“…In some experiments, mice were injected i.v. with 1e7 purified bone marrow-derived neutrophils (18), 200 μL pooled sera (12), or indicated dose of WT or D276G mutant fB in 200 μL PBS at the indicated times. For properdin activity blockade, WT mice were injected i.p.…”

“…AAA was induced in 8-to 12-wk-old male mice as previously described (12,18). Briefly, mice were anesthetized with 55-60 mg/kg i.p.…”

Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C

“…3 There is increasing evidence that cathepsin C plays a key role in a variety of diseases, including sepsis, 4 arthritis, 5 and other inflammatory disorders. [6][7][8][9][10][11][12] From knockout mice studies, it appears that cathepsin C is coexpressed and acts as a physiological activator of the neutrophil-derived serine proteases: neutrophil elastase, cathepsin G and proteinase 3,5 the mast cell chymase and trypase, 13 and the lymphocytes derived granzymes A and B.…”