Cross-Talk between the Complement Pathway and the Contact Activation System of Coagulation: Activated Factor XI Neutralizes Complement Factor H.
Animals
Blood Coagulation
Blood Platelets
/ metabolism
Complement C3b
/ metabolism
Complement Factor H
/ metabolism
Complement Pathway, Alternative
Endothelial Cells
/ metabolism
Factor XIa
/ metabolism
Fibrinogen
/ metabolism
Human Umbilical Vein Endothelial Cells
Humans
Inflammation
/ metabolism
Papio
Protein Binding
Receptor Cross-Talk
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
13
04
2020
accepted:
11
02
2021
pubmed:
4
4
2021
medline:
24
8
2021
entrez:
3
4
2021
Statut:
ppublish
Résumé
Complement factor H (CFH) is the major inhibitor of the alternative pathway of the complement system and is structurally related to beta2-glycoprotein I, which itself is known to bind to ligands, including coagulation factor XI (FXI). We observed reduced complement activation when FXI activation was inhibited in a baboon model of lethal systemic inflammation, suggesting cross-talk between FXI and the complement cascade. It is unknown whether FXI or its activated form, activated FXI (FXIa), directly interacts with the complement system. We explored whether FXI could interact with and inhibit the activity of CFH. We found that FXIa neutralized CFH by cleavage of the R341/R342 bonds. FXIa reduced the capacity of CFH to enhance the cleavage of C3b by factor I and the decay of C3bBb. The binding of CFH to human endothelial cells was also reduced after incubating CFH with FXIa. The addition of either short- or long-chain polyphosphate enhanced the capacity of FXIa to cleave CFH. FXIa also cleaved CFH that was present on endothelial cells and in the secretome from blood platelets. The generation of FXIa in plasma induced the cleavage of CFH. Moreover, FXIa reduced the cleavage of C3b by factor I in serum. Conversely, we observed that CFH inhibited FXI activation by either thrombin or FXIIa. Our study provides, to our knowledge, a novel molecular link between the contact pathway of coagulation and the complement system. These results suggest that FXIa generation enhances the activity of the complement system and thus may potentiate the immune response.
Identifiants
pubmed: 33811105
pii: jimmunol.2000398
doi: 10.4049/jimmunol.2000398
pmc: PMC8030746
mid: NIHMS1674250
doi:
Substances chimiques
Complement C3b
80295-43-8
Complement Factor H
80295-65-4
Fibrinogen
9001-32-5
Factor XIa
EC 3.4.21.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1784-1792Subventions
Organisme : NIAID NIH HHS
ID : R01 AI157037
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL101972
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL140025
Pays : United States
Informations de copyright
Copyright © 2021 by The American Association of Immunologists, Inc.
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