Killing three birds with one BPI: Bactericidal, opsonic, and anti-inflammatory functions

Abstract

Bactericidal/permeability-increasing protein (BPI) is an anti-microbial protein predominantly expressed in azurophilic granules of neutrophils. BPI has been shown to mediate cytocidal and opsonic activity against Gram-negative bacteria, while also blunting inflammatory activity of lipopolysaccharide (LPS). Despite awareness of these functions in vitro, the magnitude of the contribution of BPI to innate immunity remains unclear, and the nature of the functional role of BPI in vivo has been submitted to limited investigation. Understanding this role takes on particular interest with the recognition that autoimmunity to BPI is tightly linked to a specific infectious trigger like Pseudomonas aeruginosa in chronic lung infection. This has led to the notion that anti-BPI autoantibodies compromise the activity of BPI in innate immunity against P. aeruginosa , which is primarily mediated by neutrophils. In this review, we explore the three main mechanisms in bactericidal, opsonic, and anti-inflammatory of BPI. We address the etiology and the effects of BPI autoreactivity on BPI function. We explore BPI polymorphism and its link to multiple diseases. We summarize BPI therapeutic potential in both animal models and human studies, as well as offer therapeutic approaches to designing a sustainable and promising BPI molecule.

Bactericidal/Permeability-Increasing Protein Downregulates the Inflammatory Response in In Vivo Models of Arthritis

“…Together these results are in agreement with previous studies demonstrating that BPI displays anti-inflammatory properties in both in vitro and in vivo experimental models. For instance, a recent study reported enhanced neutrophil recruitment and inflammatory cytokines in BPI-deficient mice infected with Pseudomonas aeruginosa, which were corrected after administration of exogenous BPI [ 21 ]. In addition, it was shown that BPI prevents TNF secretion by human PBMC in response to LPS in a dose-dependent manner [ 41 ].…”

“…However, although the anti-inflammatory action of BPI is well known, this effect has only been demonstrated in the presence of bacterial infections so far. Indeed, this protein exerts an antimicrobial activity by damaging bacterial membranes, neutralizing endotoxin, and exhibiting opsonic function [ 9 , 21 ]. Otherwise, in our experiments, we used MSU or CPP crystals, which are pathogenic but not infectious agents, thus suggesting for the first time that BPI can also exert an anti-inflammatory activity in sterile inflammation.…”

“…In experimental animal models of infection, administration of recombinant BPI congeners is associated with improved outcomes and a significant increase in survival rates. Clinical studies in humans have demonstrated that treatment with recombinant amino terminal fragments of BPI neutralized endotoxin in patients with acute meningococcal disease [ 21 ]. Currently, however, the use of BPI in arthritis or similar conditions has never been evaluated.…”

Mammals' humoral immune proteins and peptides targeting the bacterial envelope: from natural protection to therapeutic applications against multidrug‐resistant Gram‐negatives

“…Mammals display a wide array of membrane‐targeting antimicrobial proteins, but only representatives with activity against at least some of the ESKAPE Gram‐negatives, and/or publications regarding their therapeutic potential are discussed here (Table 3 , Fig. 1 ): Bactericidal/permeability increasing protein (BPI) and related proteins, Group IIA secretory Phospholipase A 2 (GIIA sPLA2), and the surfactant‐associated proteins SP‐A and SP‐D, which have been reviewed recently not only in terms of their antimicrobial power but also for other interesting immunomodulatory features and implications (Floros et al ., 2021 ; Letsiou, Htwe & Dudek, 2021 ; Theprungsirikul, Skopelja‐Gardner & Rigby, 2021 ). Some antimicrobial proteins are not addressed here, either because they have poor (or untested) activity against ESKAPE Gram‐negative pathogens [for example, human skin chemerin (Banas et al ., 2013 )], or because there is uncertainty about their mechanistic action.…”

Scorpionfish BPI is highly active against multiple drug-resistantPseudomonas aeruginosaisolates from cystic fibrosis patients

“…The recombinant N-terminal fragment of human BPI (rBPI21) was shown to be highly effective against MDR Gram-negative bacteria including MDR Pa (15). However, anti-neutrophil cytoplasmic autoantibodies directed against BPI (BPI-ANCA) found in up to 83% of CF patients (16) inhibit the bactericidal function of BPI (17,18). Coherently, BPI-ANCA correlate with increased colonization with Pa (19), impaired lung function and poor prognosis (20).…”