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

Neutrophil granule proteins tune monocytic cell function

“…In addition, macrophage maturation, migratory capacity, cytokine gene expression and phagocytosis are affected by SGD in both humans and mice [14,15]. In the case of dipeptidyl peptidase I (DPPI) deficiency, which results in a loss of function of the PMN serine proteases elastase, cathepsin G and proteinase-3 [16], a secondary macrophage dysfunction is also observed [17][18][19]. PMNs from humans and mice with Chediak-Higashi syndrome are characterized by reduced degranulatory capacity [20,21], which leads to lower monocyte chemotaxis and chemokine expression [22,23].…”

BENEFICIAL EFFECT OF AN INHIBITOR OF LEUKOCYTE ELASTASE (EPI-hNE-4) IN PRESENCE OF REPEATED LUNG INJURIES

“…Fortunately, recent studies may help understanding these discrepancies. First, Adkison and colleagues (27) have shown that serine protease-deficient neutrophils do not have an intrinsic defect in their ability to transmigrate across the endothelial barrier in response to CXC-like chemokines. Consequently, the inhibition of neutrophil migration evidenced in their study in absence of serine proteases is in keeping with their concept that these proteases modulate the local release and/or processing of cytokines, and possibly of chemokines.…”

Role of serine proteases in inflammation: Bowman–Birk protease inhibitor (BBI) as a potential therapy for autoimmune diseases

“…The absence of neutrophil serine proteases prevents induction of collagen-induced arthritis in mice (Adkison et al, 2002). In another study, neutrophil elastase-deficient mice were not susceptible to an antibody-mediated autoimmune dermatosis called bullous pemphigoid disease (Liu et al, 2000).…”