TFPI-2 Protects Against Gram-Negative Bacterial Infection

Abstract

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.

Specific expression and blood kinetics for relaxin 2, lipocalin 2, and tissue factor pathway inhibitor 2 at the canine placenta and pregnant bloods

“…LCN2 could be a useful factor in the study of canine trophoblast invasiveness and may be an indicator of activity during gestation. TFPI2, called also as a matrix-associated serine protease inhibitor, has been found in human placentas, especially in the vascular endothelial cells and the microvilli of placental syncytiotrophoblasts [1,25,40]. The function of TFPI2 is proposed to promote trophoblast invasion by relating to MMP-2 and MMP-9 expressions [46].…”

Associations of tissue factor and tissue factor pathway inhibitor with organ dysfunctions in septic shock

“…Although TFPI-1 accounts for only about 30% of the total TFPI in plasma, it is considered the more potent anticoagulant form 42 . TFPI-2 might rather be relevant for host defense than for anticoagulant functions 43 . Interestingly, a releasable pool of TFPI-1 seems to derive not directly from endothelial cells but from the extravascular space 44 .…”

Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications

“…Additionally, in TFPI conditional knockout mice, TFPI deficiency worsened sepsis-induced ALI/ARDS and reduced survival rates [98]. Several reports have demonstrated that TFPI can be used in the treatment of Gram-negative bacterial infections, suggesting a therapeutic strategy targeting the coagulation pathway [100][101][102], and nebulized or injected recombinant human TFPI has been reported to mitigate both pulmonary and systemic coagulation [103,104]. However, the relationship between the efficacy of exogenous TFPI and the dosage, as well as any associated side effects, remains to be explored.…”