Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot

Krishana C. Gulla, Kshitij Gupta, Anders Krarup, P. Gál, Wilhelm J. Schwaeble, Robert B. Sim, C. David O'Connor, Krishnan Hajela

Research output: Contribution to journalArticle

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Abstract

The lectin pathway of complement is activated upon binding of mannan-binding lectin (MBL) or ficolins (FCNs) to their targets. Upon recognition of targets, the MBL-and FCN-associated serine proteases (MASPs) are activated, allowing them to generate the C3 convertase C4b2a. Recent findings indicate that the MASPs also activate components of the coagulation system. We have previously shown that MASP-1 has thrombin-like activity whereby it cleaves and activates fibrinogen and factor XIII. MASP-2 has factor Xa-like activity and activates prothrombin through cleavage to form thrombin. We now report that purified L-FCN-MASPs complexes, bound from serum to N-acetylcysteine-Sepharose, or MBL-MASPs complexes, bound to mannan-agarose, generate clots when incubated with calcified plasma or purified fibrinogen and factor XIII. Plasmin digestion of the clot and analysis using anti-D-dimer antibodies revealed that the clot was made up of fibrin and was similar to that generated by thrombin in normal human plasma. Fibrinopeptides A and B (FPA and FPB, respectively) were released after fibrinogen cleavage by L-FCN-MASPs complexes captured on N-acetylcysteine-Sepharose. Studies of inhibition of fibrinopeptide release indicated that the dominant pathway for clotting catalysed by the MASPs is via MASP-2 and prothrombin activation, as hirudin, a thrombin inhibitor that does not inhibit MASP-1 and MASP-2, substantially inhibits fibrinopeptide release. In the light of their potent chemoattractant effects on neutrophil and fibroblast recruitment, the MASP-mediated release of FPA and FPB may play a role in early immune activation. Additionally, MASP-catalysed deposition and polymerization of fibrin on the surface of micro-organisms may be protective by limiting the dissemination of infection.

Original languageEnglish
Pages (from-to)482-495
Number of pages14
JournalImmunology
Volume129
Issue number4
DOIs
Publication statusPublished - Apr 2010

Fingerprint

Mannose-Binding Protein-Associated Serine Proteases
Fibrin
Mannose-Binding Lectin
Thrombin
Sepharose
Fibrinogen
Factor XIII
Acetylcysteine
Prothrombin
Classical Pathway Complement C3 Convertase
Mannose-Binding Lectin Complement Pathway
Fibrinopeptide B
Fibrinopeptide A
Hirudins
Mannans
Factor Xa
Neutrophil Infiltration
Fibrinolysin
Chemotactic Factors
Serine Proteases

Keywords

  • Coagulation
  • Lectin pathway
  • Mannan-binding lectin
  • Mannan-binding lectin-associated serine proteases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. / Gulla, Krishana C.; Gupta, Kshitij; Krarup, Anders; Gál, P.; Schwaeble, Wilhelm J.; Sim, Robert B.; O'Connor, C. David; Hajela, Krishnan.

In: Immunology, Vol. 129, No. 4, 04.2010, p. 482-495.

Research output: Contribution to journalArticle

Gulla, KC, Gupta, K, Krarup, A, Gál, P, Schwaeble, WJ, Sim, RB, O'Connor, CD & Hajela, K 2010, 'Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot', Immunology, vol. 129, no. 4, pp. 482-495. https://doi.org/10.1111/j.1365-2567.2009.03200.x
Gulla, Krishana C. ; Gupta, Kshitij ; Krarup, Anders ; Gál, P. ; Schwaeble, Wilhelm J. ; Sim, Robert B. ; O'Connor, C. David ; Hajela, Krishnan. / Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. In: Immunology. 2010 ; Vol. 129, No. 4. pp. 482-495.
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