Tissue factor pathway inhibitor-2 (TFPI-2) has previously been characterized as an endogenous
anticoagulant.
TFPI-2 is expressed in the vast majority of cells, mainly secreted into the extracellular matrix. Recently we reported that EDC34, a C-terminal
peptide derived from
TFPI-2, exerts a broad antimicrobial activity. In the present study, we describe a previously unknown antimicrobial mode of action for the human
TFPI-2 C-terminal
peptide EDC34, mediated via binding to
immunoglobulins of the classes
IgG,
IgA,
IgE, and
IgM. In particular the interaction of EDC34 with the Fc part of
IgG is of importance since this boosts interaction between the
immunoglobulin and
complement factor C1q. Moreover, we find that the binding increases the C1q engagement of the
antigen-antibody interaction, leading to enhanced activation of the classical complement pathway during
bacterial infection. In experimental murine models of
infection and
endotoxin challenge, we show that
TFPI-2 is up-regulated in several organs, including the lung. Correspondingly,
TFPI-2-/- mice are more susceptible to pulmonary Pseudomonas aeruginosa
bacterial infection. No anti-
coagulant role of
TFPI-2 was observed in these models in vivo. Furthermore, in vivo, the mouse TFPI-2-derived C-terminal
peptide VKG24, a homolog to human EDC34 is protective against systemic Escherichia coli
bacterial infection. Moreover, in sputum from
cystic fibrosis patients
TFPI-2 C-terminal fragments are generated and found associated with
immunoglobulins. Together our data describe a previously unknown host defense mechanism and therapeutic importance of
TFPI-2 against invading Gram-negative bacterial pathogens.