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A Conformational Ch...
A Conformational Change of Complement C5 Is Required for Thrombin-Mediated Cleavage, Revealed by a Novel Ex Vivo Human Whole Blood Model Preserving Full Thrombin Activity
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- Nilsson, Per H., 1980- (författare)
- Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Avancerade material,Univ Oslo, Norway;Oslo Univ Hosp, Norway,Linnaeus Ctr Biomat Chem, BMC;HoRB
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- Johnson, Christina (författare)
- Univ Oslo, Norway;Oslo Univ Hosp, Norway
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- Quach, Quang Huy (författare)
- Univ Oslo, Norway;Oslo Univ Hosp, Norway
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- Macpherson, Alex (författare)
- UCB, UK;Univ Bath, UK
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- Durrant, Oliver (författare)
- UCB, UK;Univ Bath, UK
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- Pischke, Soeren E. (författare)
- Univ Oslo, Norway;Oslo Univ Hosp, Norway
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- Fure, Hilde (författare)
- Nordland Hosp, Norway
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- Landsem, Anne (författare)
- Nordland Hosp, Norway;Univ Tromsø, Norway
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- Bergseth, Grethe (författare)
- Nordland Hosp, Norway
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- Schjalm, Camilla (författare)
- Univ Oslo, Norway;Oslo Univ Hosp, Norway
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- Haugaard-Kedstrom, Linda M. (författare)
- Univ Copenhagen, Denmark
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- Huber-Lang, Markus (författare)
- Univ Hosp Ulm, Germany
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- van den Elsen, Jean (författare)
- Univ Bath, UK
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- Brekke, Ole-Lars (författare)
- Nordland Hosp, Norway;Univ Tromsø, Norway
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- Mollnes, Tom Eirik (författare)
- Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, Norway;Univ Tromsø, Norway;Norwegian Univ Sci & Technol, Norway
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(creator_code:org_t)
- 2021-09-15
- 2021
- Engelska.
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 207:6, s. 1641-1651
- Relaterad länk:
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https://doi.org/10.4...
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https://www.jimmunol...
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https://urn.kb.se/re...
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https://doi.org/10.4...
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Abstract
Ämnesord
Stäng
- Thrombin activation of C5 connects thrombosis to inflammation. Complement research in whole blood ex vivo necessitates anticoagulation, which potentially interferes with the inflammatory modulation by thrombin. We challenged the concept of thrombin as an activator of native C5 by analyzing complement activation and C5 cleavage in human whole blood anticoagulated with Gly-Pro-Arg-Pro (GPRP), a peptide targeting fibrin polymerization downstream of thrombin, allowing complete endogenous thrombin generation. GPRP dose-dependently inhibited coagulation but allowed for platelet activation in accordance with thrombin generation. Spontaneous and bacterial-induced complement activation by Escherichia coli and Staphylococcus aureus, analyzed at the level of C3 and C5, were similar in blood anticoagulated with GPRP and the thrombin inhibitor lepirudin. In the GPRP model, endogenous thrombin, even at supra-physiologic concentrations, did not cleave native C5, despite efficiently cleaving commercially sourced purified C5 protein, both in buffer and when added to C5-deficient serum. In normal serum, only exogenously added, commercially sourced C5 was cleaved, whereas the native plasma C5 remained intact. Crucially, affinity-purified C5, eluted under mild conditions using an MgCl2 solution, was not cleaved by thrombin. Acidification of plasma to pH # 6.8 by hydrochloric or lactic acid induced a C5 antigenic change, nonreversible by pH neutralization, that permitted cleavage by thrombin. Circular dichroism on purified C5 confirmed the structural change during acidification. Thus, we propose that pH-induced conformational change allows thrombin-mediated cleavage of C5 and that, contrary to previous reports, thrombin does not cleave plasma C5 in its native form, suggesting that thrombin cleavage of C5 may be restricted to certain pathophysiological conditions.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- Immunologi
- Immunology
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- ref (ämneskategori)
- art (ämneskategori)
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Nilsson, Per H., ...
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Johnson, Christi ...
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Quach, Quang Huy
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Macpherson, Alex
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Durrant, Oliver
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Pischke, Soeren ...
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visa fler...
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Fure, Hilde
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Landsem, Anne
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Bergseth, Grethe
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Schjalm, Camilla
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Haugaard-Kedstro ...
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Huber-Lang, Mark ...
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van den Elsen, J ...
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Brekke, Ole-Lars
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Mollnes, Tom Eir ...
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