Toggle Main Menu Toggle Search

ePrints

Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation

Lookup NU author(s): Professor David Kavanagh

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

Author(s): Blatt AZ, Saggu G, Cortes C, Herbert AP, Kavanagh D, Ricklin D, Lambris JD, Ferreira VP

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2017

Volume: 8

Online publication date: 23/11/2017

Acceptance date: 01/11/2017

ISSN (electronic): 1664-3224

Publisher: Frontiers Media

URL: https://doi.org/10.3389/fimmu.2017.01586

DOI: 10.3389/fimmu.2017.01586

PubMed id: 29218045


Altmetrics

Altmetrics provided by Altmetric


Actions

    Link to this publication


Share