A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways.
Neutrophils and complement are key sentinels of innate immunity and mediators of acute inflammation. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways. To date, the potential cross-talk between innate immunity and thrombosis and the precise molecular pathway by which complement and neutrophils trigger the coagulation process have remained elusive. In this study, we demonstrate that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the induction of tissue factor (TF), a key initiating component of the blood coagulation cascade. TF expression by neutrophils was associated with an enhanced procoagulant activity, as verified by a modified prothrombin time assay inhibited by anti-TF mAb. Inhibition studies using the complement inhibitor compstatin revealed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF-dependent coagulant activity. Blockade studies using a selective C5a receptor antagonist and stimulation of neutrophils with recombinant human C5a demonstrated that C5a, and its receptor C5aR, mediate the expression of TF in neutrophils and thereby significantly enhance the procoagulant activity of neutrophils exposed to APS serum. These results identify a novel cross-talk between the complement and coagulation cascades that can potentially be exploited therapeutically in the treatment of APS and other complement-associated thrombotic diseases.
Ritis
Konstantinos
K
First Division of Internal Medicine, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece. ritis2@otenet.gr
Doumas
Michael
M
Mastellos
Dimitrios
D
Micheli
Anastasia
A
Giaglis
Stavros
S
Magotti
Paola
P
Rafail
Stavros
S
Kartalis
Georgios
G
Sideras
Paschalis
P
Lambris
John D
JD
D016736:Antiphospholipid Syndrome / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology*; D015153:Blotting, Western; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D009504:Neutrophils / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020239:Receptor Cross-Talk / Q000502:physiology*; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism
D007074:Immunoglobulin G; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D013925:Thromboplastin