Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor.
Neutrophil dysfunction, resulting in inefficient bacterial clearance, is a feature of several serious medical conditions, including cystic fibrosis (CF) and sepsis. Poorly controlled neutrophil serine protease (NSP) activity and complement activation have been implicated in this phenomenon. The capacity for excess NSP secretion and complement activation to influence the expression and function of the important neutrophil-activating receptor C5aR was investigated. Purified NSPs cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 cleaved C5aR to a 26- to 27-kDa membrane-bound fragment, thereby inactivating its C5a-induced signaling ability. In a supernatant transfer assay, NSPs released from neutrophils in response to C5a induced the cleavage of the C5aR on unstimulated cells. Stimulation of myeolomonocytic U937 cells and purified neutrophils with C5a resulted in downregulation of the C5aR on these cells, which, in the case of U937 cells, was largely caused by NSP-mediated cleavage of C5aR, but in the case of neutrophils, intracellular degradation was likely the main mediator in addition to a small role for NSPs. CG and NE in bronchoalveolar lavage fluid from CF patients both contributed to C5aR cleavage. We propose two converging models for C5a- and NSP-mediated neutrophil dysfunction whereby C5aR cleavage is induced by NSPs, secreted in response to: 1) excess C5a generation or other stimuli; or 2) necrosis. The consequent impairment of C5aR activity contributes to suboptimal local neutrophil priming and bacterial clearance. NSP inhibitors with specificity for both CG and NE may aid the treatment of pathologies associated with neutrophil dysfunction including sepsis and CF.
Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;
Carmen W
CW
van den Berg
Denise V
DV
Tambourgi
Howard W
HW
Clark
S Julie
SJ
Hoong
O Brad
OB
Spiller
Eamon P
EP
McGreal
D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D056649:Cathepsin G / Q000378:metabolism; D002460:Cell Line; D002648:Child; D003167:Complement Activation / Q000276:immunology*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D053146:Myeloblastin / Q000378:metabolism; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D020298:U937 Cells
C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D057057:Serine Proteases; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin