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Inactivate the C5a Receptor Neutrophil Serine Proteases Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor This information is current as Carmen W. van den Berg, Denise V. Tambourgi, Howard of September 27, 2021. W. Clark, S. Julie Hoong, O. Brad Spiller and Eamon P. McGreal J Immunol 2014; 192:1787-1795; Prepublished online 20 January 2014; doi: 10.4049/jimmunol.1301920 Downloaded from http://www.jimmunol.org/content/192/4/1787 References This article cites 44 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/192/4/1787.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor Carmen W. van den Berg,* Denise V. Tambourgi,† Howard W. Clark,‡ S. Julie Hoong,* O. Brad Spiller,* and Eamon P. McGreal* 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 impli- cated 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 unstimu- lated cells. Stimulation of myeolomonocytic U937 cells and purified neutrophils with C5a resulted in downregulation of the C5aR on Downloaded from 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 neu- trophil 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 clear- ance. NSP inhibitors with specificity for both CG and NE may aid the treatment of pathologies associated with neutrophil dys- http://www.jimmunol.org/ function including sepsis and CF. The Journal of Immunology, 2014, 192: 1787–1795. ell-regulated neutrophil activity is critical for the ef- IL-6, CXCR1, and soluble IL-6R (4, 5)] and innate immune rec- ficient clearance of infectious microbes; however, ognition molecules including the complement receptor (CR) for W uncontrolled neutrophil activity also contributes to C3b (CR1), its ligand C3bi (6, 7), and C-type lectins including neutrophil dysfunction, characterized by impaired clearance of surfactant proteins A and D (8, 9). NSP-mediated loss of CXCR1 pathogens, leading to chronic infection or death. Secreted actively (4) and CR1 (6) on neutrophils results in reduced phagocytosis (as a consequence of cell activation) or passively (as a consequence of Pseudomonas aeruginosa, which may partly explain the high by guest on September 27, 2021 of necrotic cell death), neutrophil serine proteases (NSPs; e.g., prevalence of chronic infection with P. aeruginosa and other neutrophil elastase [NE], cathepsin G [CG], and proteinase 3 [PR3]) bacteria in individuals with neutrophil-dominated airway disease, are major contributors to neutrophil dysfunction. NE is considered including CF. a major contributor to a range of pulmonary pathologies, includ- The importance of the complement system in clearing bacterial ing cystic fibrosis (CF) (1–3), and is an important therapeutic infection is well recognized. C3b opsonizes bacteria for phago- target (3). Under well-controlled conditions in otherwise healthy cytosis via CRs CR1 and CR3. C5a is a powerful chemoattractant individuals, NSPs contribute to the effective control of infection. for neutrophils, but also enhances C3b-induced phagocytosis However, excessive and poorly regulated NSP activity contributes and intracellular killing of bacteria (10, 11). C5a mediates its ef- to disease in a number of ways (3). In addition to their direct fects by interaction with the C5a receptor (C5aR/CD88), a seven- elastolytic activity toward lung tissue, NSPs also have the capacity transmembrane G-protein–coupled receptor (GPCR), which is highly to substantially modulate local inflammatory responses through expressed on cells of myeloid origin (12). Both C5-deficient proteolysis of cytokines and chemokines and their receptors [e.g., and C5aR-knockout mice exhibit impaired lung clearance of P. aeruginosa (13–15). Interestingly, knockout of C5aR reveals a critical role for this receptor, because clearance and control of *Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; †Immunochemistry Laboratory, bacterial infection and mortality from P. aeruginosa infection is Butantan Institute, Sa˜o Paulo 05503-900, Brazil; and ‡Department of Child Health, significantly elevated in these mice, despite increased neutrophil Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom influx. Blocking C5aR also inhibits phagocytosis and intracellular Escherichia coli Received for publication July 18, 2013. Accepted for publication December 2, 2013. killing of by human neutrophils (10). The im- portance of the C5a/C5aR system to antimicrobial defense is S.J.H. received a Wales Heart Research Institute, Cardiff University, professional training year scholarship. underlined by the elaborate strategies evolved by bacteria to avoid Address correspondence and reprint requests to Dr. Carmen W. van den Berg, Insti- the complement system, including blockade of C5a generation tute of Molecular and Experimental Medicine, School of Medicine, Cardiff Univer- and C5aR function (16). However, excess complement activation sity, Cardiff CF14 4XN, U.K. E-mail address: [email protected] and C5a generation is also associated with numerous patholo- Abbreviations used in this article: BALF, bronchoalveolar lavage fluid; CF, cystic gies, including ’09 and Unnewher ‘13 (11, 12). Paradoxically, fibrosis; CG, cathepsin G; CR, complement receptor; CytoD, cytochalasin D; GPCR, G-protein–coupled receptor; KHB, Krebs/HEPES/BSA; NE, neutrophil elastase; excess C5a has been observed to impair neutrophil function NSP, neutrophil serine protease; PMN, polymorphonuclear neutrophil; PR3, protein- and is associated with impaired complement-dependent phago- ase 3. cytosis and reduced C5aR expression both in vivo in animal Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 models and ex vivo in cells from human sepsis patients (17–21) www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301920 1788 NEUTROPHIL DYSFUNCTION CAUSED BY NSP CLEAVAGE OF C5aR in whom relative expression of C5aR is suggested to be of prog- and blotted onto Hybond Nitrocellulose (GE Healthcare UK, Little Chalfont, nostic significance (11). U.K.). C5aR was detected as described (22) using mAb S5/1 or polyclonal The mechanisms of C5a-induced neutrophil dysfunction and anti-C5aR. Precision Plus All Blue standards (Bio-Rad, Hemel Hempstead, U.K.) were used to calculate the molecular weights of the bands. regulation of C5aR expression have not yet been elucidated. NSPs have been shown to proteolytically reduce the expression of several Flow cytometry cell-surface molecules involved in immunity, including CXCR1 Cell-surface C5aR expression was detected by flow cytometry as described (IL-8RA), CR1, CD16, CD43, and TNFRII, but their impact on (22) using mAb S5/1, and fluorescence was measured on an Accuri flow C5aR expression has not been investigated. Proteolytic cleavage cytometer (BD Biosciences). Results are expressed as average of mean of 6 and inactivation of C5aR has been demonstrated by a variety of arbitrary fluorescent intensity SD of experiments carried out in triplicate. endogenous and exogenous proteases, including an endogenous Calcium flux measurements metalloprotease, activated by the action of Loxosceles spider venom Cells (at 107c/ml) were loaded with 2 mM fura 2-AM for 30 min at room sphingomyelinase D, a serine protease from Porphyromonas gin- temperature. Cells were washed and resuspended in KHB buffer and incu- givalis, and a metalloprotease from venom
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