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Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor

Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor
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.

Bronchoalveolar Lavage Fluid, Cathepsin G, Cell Line, Child, Complement Activation, Humans, Leukocyte Elastase, Myeloblastin, Neutrophil Activation, Neutrophils, Receptor, Anaphylatoxin C5a, Serine Proteases, Signal Transduction, U937 Cells, Journal Article, Research Support, Non-U.S. Gov't
0022-1767
1787-1795
van den Berg, Carmen W.
37f71a14-a3ac-4622-986f-e8b13d6677ff
Tambourgi, Denise V.
63f5f318-110f-4261-863b-9a343e79cca6
Clark, Howard W.
70550b6d-3bd7-47c6-8c02-4f43f37d5213
Hoong, S. Julie
c9b06064-13f7-4d98-a6ae-74e6d40f381f
Spiller, O. Brad
a802a26a-804c-4839-a25e-830e3856e852
McGreal, Eamon P.
6ca021ea-09c4-4f08-888f-e82330d7a413
van den Berg, Carmen W.
37f71a14-a3ac-4622-986f-e8b13d6677ff
Tambourgi, Denise V.
63f5f318-110f-4261-863b-9a343e79cca6
Clark, Howard W.
70550b6d-3bd7-47c6-8c02-4f43f37d5213
Hoong, S. Julie
c9b06064-13f7-4d98-a6ae-74e6d40f381f
Spiller, O. Brad
a802a26a-804c-4839-a25e-830e3856e852
McGreal, Eamon P.
6ca021ea-09c4-4f08-888f-e82330d7a413

van den Berg, Carmen W., Tambourgi, Denise V., Clark, Howard W., Hoong, S. Julie, Spiller, O. Brad and McGreal, Eamon P. (2014) Mechanism of neutrophil dysfunction: neutrophil serine proteases cleave and inactivate the C5a receptor. The Journal of Immunology, 192 (4), 1787-1795. (doi:10.4049/jimmunol.1301920).

Record type: Article

Abstract

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.

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More information

Accepted/In Press date: 2 December 2013
e-pub ahead of print date: 7 February 2014
Published date: 15 February 2014
Keywords: Bronchoalveolar Lavage Fluid, Cathepsin G, Cell Line, Child, Complement Activation, Humans, Leukocyte Elastase, Myeloblastin, Neutrophil Activation, Neutrophils, Receptor, Anaphylatoxin C5a, Serine Proteases, Signal Transduction, U937 Cells, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 418651
URI: https://eprints.soton.ac.uk/id/eprint/418651
ISSN: 0022-1767
PURE UUID: 7e69116f-4ca3-425b-9df1-f55c35576f3d

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Date deposited: 14 Mar 2018 17:30
Last modified: 13 Mar 2019 18:48

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Contributors

Author: Carmen W. van den Berg
Author: Denise V. Tambourgi
Author: Howard W. Clark
Author: S. Julie Hoong
Author: O. Brad Spiller
Author: Eamon P. McGreal

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