The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease

Abstract

Gram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentially induce severe pathophysiology, necessitating controlled initiation and resolution of endotoxin-induced inflammation to maintain host integrity. The bactericidal/permeability-increasing protein (BPI) is a pluripotent protein expressed, in humans, mainly neutrophils. BPI exhibits strong antimicrobial activity against GNB and potent endotoxin-neutralizing activity. BPI mobilized with neutrophils in response to invading GNB can promote intracellular and extracellular bacterial killing, endotoxin neutralization and clearance, and delivery of GNB outer membrane antigens to dendritic cells. Tissue expression by dermal fibroblasts and epithelia could further amplify local levels of BPI and local interaction with GNB and endotoxin, helping to constrain local tissue infection and inflammation and prevent systemic infection and systemic inflammation. This review article focuses on the structural and functional properties of BPI with respect to its contribution to host defense during GNB infections and endotoxin-induced inflammation and the genesis of autoantibodies against BPI that can blunt BPI activity and potentially contribute to chronic inflammatory disease.

Figure 1

Schematic structure of outer membrane (OM) blebbing Gram-negative bacteria (GNB) (A), the envelope of Gram-negative bacteria (B) and lipo-poly (oligo)-saccharides (C)

Figure 2. Structure and function of the bactericidal/permeability-increasing protein

Ribbon diagram of the structure of the bactericidal/permeability-increasing protein including bound host phospholipids (*)(modified after [46]), major antibacterial functions are associated with the amino-and carboxy- terminal domains are indicated.

Figure 3. Interactions of BPI with Gram-negative bacteria in tissue settings

The initial interactions between Gram-negative bacteria, endotoxin and BPI normally takes place in the tissue. BPI is present on the apical and basolateral surfaces of the epithelium but if levels of BPI expression at these sites are great enough to increase local defences against invading GNB is unknown. Fibroblasts located under the epithelial lining also express BPI and could serve as a second barrier against GNB and endotoxin. However, the major source of BPI in tissue is derived from recruited and activated neutrophils. BPI can promote delivery of GNB remnants (e.g. OM blebs) to dendritic cells, facilitating induction of T-cell-dependent antibacterial immunity. BPI expression in fibroblasts and epithelia later in the immune response by IL-4 and lipoxins, respectively [38, 39] may further promote elimination of GNB and resolution of endotoxin-induced inflammation. Dendritic cells have not only the potential to ingest bacteria but can also internalize and process OM blebs and BPI delivered to them and provide a link to the adaptive immune system. Abbreviations: PMN polymorphonuclear neutrophil granulocyte, GNB Gram-negative bacteria, Mono monocyte, FB fibroblast, DC dendritic cell, BPI bactericidal/permeability increasing protein, OM blebs outer membrane vesicles of GNB.

Figure 4. Roles of BPI during GNB infection

Role of BPI in the interaction of GNB and OM blebs with neutrophil granulocytes and monocytes (A). BPI can opsonize GNB and target them to be phagocytosed by PMN. It can contribute to intracellular killing of ingested GNB and also to extracellular bacterial killing when released to the extracellular space by PMN. Single endotoxin molecules from OM blebs or other endotoxin containing remnants of GNB can be extracted and processed by the LBP/CD14/MD-2/TLR-4 pathway resulting an activation of CD-14 positive monocytes. In contrast, BPI bound endotoxin is not accessible for LBP/CD14 mediated LOS/LPS extraction and does not cause an inflammatory response in monocytes [81, 82, 107]. Role of BPI in the interaction of OM blebs with dendritic cells (B). BPI can promote CD14-independent delivery of OM blebs to dendritic cells (DC). In parallel, LBP and sCD14 can promote MDDC activation by extraction and delivery of endotoxin to MD-2/TLR4 [108]. Subsequently, the ability of BPI and LBP to interact with the same OM bleb could allow coincidental enhancement of antigen delivery by BPI and LBP/sCD14-dependent cell activation and could thereby promote antigen-presenting functions of DC. Abbreviations: BPI Bactericidal/permeability-increasing protein, GNB Gram negative bacteria, LBP Lipopolysaccharides binding protein, CD14 either membrane bound or soluble CD14, Blebs outer membrane vesicles of GNB, LOS/LPS lipooligosaccharide or lipopolysaccharide, MD-2 Myeloid Differentiation-2, TLR-4 TOLL-like receptor-4

Figure 5. Prevalence of BPI-autoantibodies in selected inflammatory diseases (modified after [125])

Shown is the prevalence of BPI-ANCA in selected studies of healthy persons and patients with infectious diseases, rheumatic diseases, inflammatory bowel diseases and immunodeficiency [17, 18, 115, 118, 119, 126]. Abbreviations: HIV human immunodeficiency virus; ReA reactive arthritis; TAP transporter associated with antigen presentation