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Interplay between fibrinolysis and complement: plasmin cleavage of iC 3b modulates immune responses
Author(s) -
Foley J. H.,
Peterson E. A.,
Lei V.,
Wan L. W.,
Krisinger M. J.,
Conway E. M.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12837
Subject(s) - ic3b , plasmin , chemistry , complement factor i , microbiology and biotechnology , opsonin , complement receptor , complement system , phagocytosis , immune system , biochemistry , biology , immunology , enzyme
Summary Background The plasmin(ogen) and complement systems are simultaneously activated at sites of tissue injury, participating in hemostasis, wound healing, inflammation and immune surveillance. In particular, the C3 proteolytic fragment, iC 3b, and its degradation product C3dg, which is generated by cleavage by factor I ( FI ) and the cofactor complement receptor CR 1, are important in bridging innate and adaptive immunity. Via a thioester ( TE ) bond, iC 3b and C3dg covalently tag pathogens, modulating phagocytosis and adaptive immune responses. Objective To examine plasmin‐mediated proteolysis of iC 3b, and to evaluate the functional consequences, comparing the effects with products generated by FI / CR 1 cleavage of iC 3b. Methods Dose‐dependent and time‐dependent plasmin‐mediated cleavage of iC 3b were characterized by analytical gel electrophoresis. The properties of the resultant TE bond‐containing fragments on phagocytosis and induction of pro‐inflammatory cytokines were measured in cell culture systems. Results At low concentrations, plasmin effectively cleaves iC 3b, but at numerous previously undescribed sites, giving rise to novel C3c‐like and C3dg‐like moieties, the latter of which retain the TE bond. When attached to zymosan or erythrocytes and exposed to THP ‐1 macrophages, the C3dg‐like proteins behave almost identically to the bona fid e C3dg, yielding less phagocytosis as compared with the opsonin iC 3b, and more macrophage secretion of the pro‐inflammatory cytokine, IL ‐12. Conclusion Plasmin cleavage of iC 3b provides a complement regulatory pathway that is as efficient as FI / CR 1 but does not require a cellular cofactor.