Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response

Abstract

Neutrophil granulocytes are important mediators of innate immunity, but also participate in the pathogenesis of (auto)inflammatory diseases. Neutrophils express a specific set of proteolytic enzymes, the neutrophil serine proteases (NSPs), which are stored in cytoplasmic granules and can be secreted into the extra- and pericellular space upon cellular activation. These NSPs, namely cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3), have early been implicated in bacterial defense. However, NSPs also regulate the inflammatory response by specifically altering the function of cytokines and chemokines. For instance, PR3 and NE both inactivate the anti-inflammatory mediator progranulin, which may play a role in chronic inflammation. Here, we provide a concise update on NSPs as modulators of inflammation and discuss the biological and pathological significance of this novel function of NSPs. Mounting evidence support an important proinflammatory function for PR3, which may have been underestimated in the past.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-010-0677-3) contains supplementary material, which is available to authorized users.

The adaptor ASC exacerbates lethal Listeria monocytogenes infection by mediating IL‐18 production in an inflammasome‐dependent and ‐independent manner

“…Our results suggest that the elevation of serum NSP activity is induced during lethal L. monocytogenes infection in an ASC-dependent, caspase-1-independent manner. NSPs that include PR3, neutrophil elastase, and cathepsin G are involved in the killing of microbial pathogens, regulation of the activity of cytokines and chemokines, cleavage of extracellular matrix components, and so on; and they have protective and pathological roles in infections, inflammation, and autoimmune diseases [46]. Considering the importance of NSPs in a variety of pathophysiological conditions, the mechanism by which ASC contributes to the elevation of serum NSP activity is of considerable interest, but it remains unknown.…”

“…It is, however, not clear where and how PR3 processes pro-IL-18 into the mature form during L. monocytogenes infection in vivo. Active PR3 is released from activated neutrophils or binds to the cell surface [11,46]. Accordingly, PR3 presumably processes circulating or local pro-IL-18 that is released, for example, from dead host cells.…”

Proteinase 3–dependent caspase-3 cleavage modulates neutrophil death and inflammation

“…The purity of neubacterial activity, but are also emerging as important mediators of the inflammatory process (15,23,(31)(32)(33)(34). PR3 can convert or activate many inflammatory molecules, such as IL-8, IL-32, IL-1β, TNF-α, or the antiinflammatory progranulin PGRN (32,35). In addition, PR3 is one of the antigens recognized by anti-neutrophil cytoplasmic antibodies (ANCAs) present in Wegener's granulomatosis.…”

The NLRP3/ASC/Caspase‐1 axis regulates IL‐1β processing in neutrophils

“…Phagocytosis of microorganisms leads to the production of reactive oxygen species within the phagolysosome that displays direct microbicidal activity. Moreover, neutrophils harbor pre-loaded cytoplasmic granules that contain large amounts of antimicrobial serine proteases that are released into the extracellular space upon degranulation [1]. In addition, neutrophils can also undergo a special type of cell death that is accompanied by the release of their own nuclear contents into the extracellular space, which leads to the formation of so-called neutrophil extracellular traps (NETs), that also display direct antimicrobial function [2].…”