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Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation
Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndro...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703703/ https://www.ncbi.nlm.nih.gov/pubmed/29218045 http://dx.doi.org/10.3389/fimmu.2017.01586 |
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author | Blatt, Adam Z. Saggu, Gurpanna Cortes, Claudio Herbert, Andrew P. Kavanagh, David Ricklin, Daniel Lambris, John D. Ferreira, Viviana P. |
author_facet | Blatt, Adam Z. Saggu, Gurpanna Cortes, Claudio Herbert, Andrew P. Kavanagh, David Ricklin, Daniel Lambris, John D. Ferreira, Viviana P. |
author_sort | Blatt, Adam Z. |
collection | PubMed |
description | Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism. Utilizing recombinant fragments of FH spanning the entire length of the protein, we mapped the regions of FH most critical for limiting AP activity on the surface of isolated human platelets and neutrophils, as well as the regions most critical for regulating PGA formation in human whole blood stimulated with thrombin receptor-activating peptide (TRAP). FH domains 19–20 were the most critical for limiting AP activity on platelets, neutrophils, and at the platelet/granulocyte interface. The role of FH in PGA formation was attributed to its ability to regulate AP-mediated C5a generation. AHUS-related mutations in domains 19–20 caused differential effects on control of PGA formation and AP activity on platelets and neutrophils. Our data indicate FH C-terminal domains are key for regulating PGA formation, thus increased FH protection may have a beneficial impact on diseases characterized by increased PGA formation, such as cardiovascular disease. Additionally, aHUS-related mutations in domains 19–20 have varying effects on control of TRAP-mediated PGA formation, suggesting that some, but not all, aHUS-related mutations may cause increased PGA formation that contributes to excessive thrombosis in patients with aHUS. |
format | Online Article Text |
id | pubmed-5703703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57037032017-12-07 Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation Blatt, Adam Z. Saggu, Gurpanna Cortes, Claudio Herbert, Andrew P. Kavanagh, David Ricklin, Daniel Lambris, John D. Ferreira, Viviana P. Front Immunol Immunology Platelet/granulocyte aggregates (PGAs) increase thromboinflammation in the vasculature, and PGA formation is tightly controlled by the complement alternative pathway (AP) negative regulator, Factor H (FH). Mutations in FH are associated with the prothrombotic disease atypical hemolytic uremic syndrome (aHUS), yet it is unknown whether increased PGA formation contributes to the thrombosis seen in patients with aHUS. Here, flow cytometry assays were used to evaluate the effects of aHUS-related mutations on FH regulation of PGA formation and characterize the mechanism. Utilizing recombinant fragments of FH spanning the entire length of the protein, we mapped the regions of FH most critical for limiting AP activity on the surface of isolated human platelets and neutrophils, as well as the regions most critical for regulating PGA formation in human whole blood stimulated with thrombin receptor-activating peptide (TRAP). FH domains 19–20 were the most critical for limiting AP activity on platelets, neutrophils, and at the platelet/granulocyte interface. The role of FH in PGA formation was attributed to its ability to regulate AP-mediated C5a generation. AHUS-related mutations in domains 19–20 caused differential effects on control of PGA formation and AP activity on platelets and neutrophils. Our data indicate FH C-terminal domains are key for regulating PGA formation, thus increased FH protection may have a beneficial impact on diseases characterized by increased PGA formation, such as cardiovascular disease. Additionally, aHUS-related mutations in domains 19–20 have varying effects on control of TRAP-mediated PGA formation, suggesting that some, but not all, aHUS-related mutations may cause increased PGA formation that contributes to excessive thrombosis in patients with aHUS. Frontiers Media S.A. 2017-11-23 /pmc/articles/PMC5703703/ /pubmed/29218045 http://dx.doi.org/10.3389/fimmu.2017.01586 Text en Copyright © 2017 Blatt, Saggu, Cortes, Herbert, Kavanagh, Ricklin, Lambris and Ferreira. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Blatt, Adam Z. Saggu, Gurpanna Cortes, Claudio Herbert, Andrew P. Kavanagh, David Ricklin, Daniel Lambris, John D. Ferreira, Viviana P. Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title | Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title_full | Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title_fullStr | Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title_full_unstemmed | Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title_short | Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation |
title_sort | factor h c-terminal domains are critical for regulation of platelet/granulocyte aggregate formation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703703/ https://www.ncbi.nlm.nih.gov/pubmed/29218045 http://dx.doi.org/10.3389/fimmu.2017.01586 |
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