A Novel Role for the Bactericidal/Permeability Increasing Protein in Interactions of Gram-Negative Bacterial Outer Membrane Blebs with Dendritic Cells

Abstract

The bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role for BPI in clearance of cell-free endotoxin has also been suggested based on studies with purified endotoxin aggregates and blood monocytes. Because the interaction of BPI with cell-free endotoxin, during infection, occurs mainly in tissue and most likely in the form of shed bacterial outer membrane vesicles (“blebs”), we examined the effect of BPI on interactions of metabolically labeled ([14C]-acetate) blebs purified from Neisseria meningitidis serogroup B with either human monocyte-derived macrophages or monocyte-derived dendritic cells (MDDC). BPI produced a dose-dependent increase (up to 3-fold) in delivery of 14C-labeled blebs to MDDC, but not to monocyte-derived macrophages in the presence or absence of serum. Both, fluorescently labeled blebs and BPI were internalized by MDDC under these conditions. The closely related LPS-binding protein, in contrast to BPI, did not increase association of the blebs with MDDC. BPI-enhanced delivery of the blebs to MDDC did not increase cell activation but permitted CD14-dependent signaling by the blebs as measured by changes in MDDC morphology, surface expression of CD80, CD83, CD86, and MHC class II and secretion of IL-8, RANTES, and IP-10. These findings suggest a novel role of BPI in the interaction of bacterial outer membrane vesicles with dendritic cells that may help link innate immune recognition of endotoxin to Ag delivery and presentation.

The role for neutrophil extracellular traps in cystic fibrosis autoimmunity

“…The C-terminal domain of BPI mediates the interaction of bacterial proteins with DCs (42). Based on our finding that anti-BPI IgG reactivity is specific to the CTBPI, we postulated that BPI cleavage might facilitate its delivery to the DCs in the context of NETosis and so lead to the breaking of tolerance.…”

Virulence and Immunomodulatory Roles of Bacterial Outer Membrane Vesicles

“…For instance, bactericidal/permeability-increasing protein (BPI), but not LPS binding protein (LBP), enhanced the uptake of N. meningitidis vesicles (122). These interactions were surprisingly selective, since the same did not occur for macrophages, and BPI did not promote similar interactions of free lipooligosaccharide aggregates with the dendritic cells.…”

“…In a similar LPS binding study, Schultz et al investigated the role of BPI in binding Neisseria OM vesicle-derived LPS. Those authors observed that BPI binding of LPS was required for the OM vesicle interaction with dendritic cells, leading to CD14-mediated signaling and the expression of proinflammatory cytokines (122).…”

Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals

“…CD14 ϩ CD16 ϩ inflammatory monocytes are intrinsically involved in host defense, responding directly to invading pathogens through their transcription and release of multiple cytokines, promoting initiation of the acute phase response. In contrast, CD14 ϩϩ classic monocytes primarily act as scavengers, aiding in the neutralization of unbound LPS (65,86) and removal of apoptotic cells as part of the mononuclear phagocyte system (46). At rest, a majority of the CD14 ϩ CD16 ϩ monocytes are not present in the peripheral circulation but reside in the marginal pool and are released into the peripheral circulation via catecholaminemediated sympathetic mechanisms (78).…”