Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis
April M. Adkison, … , Diane G. Kelley, Christine T.N. Pham
April M. Adkison, … , Diane G. Kelley, Christine T.N. Pham
Published February 1, 2002
Citation Information: J Clin Invest. 2002;109(3):363-371. https://doi.org/10.1172/JCI13462.
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Article

Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis

Abstract

Leukocyte recruitment in inflammation is critical for host defense, but excessive accumulation of inflammatory cells can lead to tissue damage. Neutrophil-derived serine proteases (cathepsin G [CG], neutrophil elastase [NE], and proteinase 3 [PR3]) are expressed specifically in mature neutrophils and are thought to play an important role in inflammation. To investigate the role of these proteases in inflammation, we generated a mouse deficient in dipeptidyl peptidase I (DPPI) and established that DPPI is required for the full activation of CG, NE, and PR3. Although DPPI–/– mice have normal in vitro neutrophil chemotaxis and in vivo neutrophil accumulation during sterile peritonitis, they are protected against acute arthritis induced by passive transfer of monoclonal antibodies against type II collagen. Specifically, there is no accumulation of neutrophils in the joints of DPPI–/– mice. This protective effect correlates with the inactivation of neutrophil-derived serine proteases, since NE–/– × CG–/– mice are equally resistant to arthritis induction by anti-collagen antibodies. In addition, protease-deficient mice have decreased response to zymosan- and immune complex–mediated inflammation in the subcutaneous air pouch. This defect is accompanied by a decrease in local production of TNF-α and IL-1β. These results implicate DPPI and polymorphonuclear neutrophil–derived serine proteases in the regulation of cytokine production at sites of inflammation.

Authors

April M. Adkison, Sofia Z. Raptis, Diane G. Kelley, Christine T.N. Pham

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In vitro PMN function and in vivo response to thioglycollate in the abse...
In vitro PMN function and in vivo response to thioglycollate in the absence of DPPI. (a) Bone marrow–derived PMNs from WT and DPPI–/– mice were allowed to migrate across a filter in response to 10–4 M fMLP, 2% zymosan-activated rat serum (ZAS), or 3 μg/ml rhIL-8. The number of cells that migrated was expressed as a percentage of total PMNs. Values represent the mean ± SEM of at least three animals. (b) Superoxide production by PMNs in response to PMA, expressed as nmol of O2– generated per 106 PMNs (n > 3 per genotype). The number of PMNs and macrophages recruited in response to intraperitoneal injection of thioglycollate is normal in DPPI–/– mice at 4 hours (c) 24 hours (d) and 120 hours (e).The slightly lower number of macrophages at 120 hours after thioglycollate injection in the DPPI–/– mice did not reach statistical significance (n = 4–5 mice per genotype). Mph, macrophages.