TFPI inhibits lectin pathway of complement activation by direct interaction with MASP-2

Eur J Immunol. 2015 Feb;45(2):544-50. doi: 10.1002/eji.201445070. Epub 2014 Nov 27.


The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.

Keywords: Complement inhibition; Complement-coagulation crosstalk; MASP-2; TFPI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Chromogenic Compounds
  • Complement C1r / chemistry
  • Complement C1r / immunology
  • Complement C1s / chemistry
  • Complement C1s / immunology
  • Complement C4 / chemistry
  • Complement C4 / immunology*
  • Complement Pathway, Mannose-Binding Lectin*
  • Humans
  • Immunoassay
  • Lipoproteins / chemistry
  • Lipoproteins / genetics
  • Lipoproteins / immunology*
  • Mannose-Binding Protein-Associated Serine Proteases / antagonists & inhibitors*
  • Mannose-Binding Protein-Associated Serine Proteases / chemistry
  • Mannose-Binding Protein-Associated Serine Proteases / immunology
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / genetics
  • Serine Proteinase Inhibitors / immunology*
  • Solutions


  • Antibodies, Monoclonal
  • Chromogenic Compounds
  • Complement C4
  • Lipoproteins
  • Recombinant Proteins
  • Serine Proteinase Inhibitors
  • Solutions
  • lipoprotein-associated coagulation inhibitor
  • MASP1 protein, human
  • MASP2 protein, human
  • Mannose-Binding Protein-Associated Serine Proteases
  • Complement C1r
  • Complement C1s