Synthetic Cationic Peptide IDR-1018 Modulates Human Macrophage Differentiation

Pena, Olga M.; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D.; Hancock, Robert E. W.

doi:10.1371/journal.pone.0052449

Cited by 81 publications

(70 citation statements)

References 47 publications

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“…We found that IDR-1018 was bactericidal even in the presence of physiologic ion levels, induced production of MCP-1, recruited macrophages to the site of infections, and blunted excess production of proinflammatory cytokines and MCP-1 induced by LPS in vitro or by in vivo infection with S aureus. However, the immunomodulatory effects of IDR-1018 were more complex than previously appreciated [1,32,42]. For example, our study was the first demonstration that IDR-1018 can blunt production of MCP-1.…”

Section: Discussionmentioning

confidence: 58%

“…Moreover, HDPs can also modulate cytokine production to control the inflammatory response [14,15,19,28,38] and thereby may reduce the risk of developing inflammatory osteolysis. IDR-1018 is one of the most attractive of the HDPs [1,26,30,32,37,39,42]. The purposes of our study were therefore (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to S aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate.…”

Section: Discussionmentioning

confidence: 99%

“…Innate defense regulator peptide-1018 (IDR-1018) is a synthetic 12-amino acid derivative of bactenecin, a bovine HDP [42]. IDR-1018 can directly kill bacteria [42], can modulate differentiation and activation of macrophages and neutrophils, thereby regulating their production of chemokines and cytokines [1,26,30,32,37,42], can reduce soft tissue infections [1,37], and can disrupt bacterial biofilms [25,35]. IDR-1018 was chosen as the focus of this study because it is the most potent IDR that has been described [37] and is therefore an attractive agent to potentially reduce orthopaedic infections and inflammatory osteolysis around orthopaedic implants.…”

Section: Introductionmentioning

confidence: 99%

“…However, orthopaedic infections can be especially difficult to combat [18,24] and IDRs have not been tested in that setting. Moreover, the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide [32,42], which is exclusively produced by Gram-negative bacteria.…”

Section: Introductionmentioning

confidence: 99%

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Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Choe

Narayanan

Gandhi

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Innate defense regulator peptide-1018 (IDR-1018) is a 12-amino acid, synthetic, immunomodulatory host defense peptide that can reduce soft tissue infections and is less likely to induce bacterial resistance than conventional antibiotics. However, IDRs have not been tested on orthopaedic infections and the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide, which is exclusively produced by Gram-negative bacteria. Questions/purposes We sought (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to Staphylococcus aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate. Methods In vitro effects of IDR-1018 on S aureus were assessed by determining minimum inhibitory concentrations in bacterial broth without and with supplementation of physiologic ion levels. In vitro effects of IDR-1018 on macrophages were determined by measuring production of monocyte chemoattractant protein-1 (MCP-1) and proinflammatory cytokines by enzyme-linked immunosorbent assay. In vivo effects of IDR-1018 were determined in a murine model of S aureus implant infection by quantitating bacterial burden, macrophage recruitment, MCP-1, proinflammatory cytokines, and osseointegration in nine mice per group on Day 1 postimplantation and 20 mice per group on Day 15 postimplantation. Results IDR-1018 demonstrated antimicrobial activity by directly killing S aureus even in the presence of physiologic ion levels, increasing recruitment of macrophages to the site of infections by 40% (p = 0.036) and accelerating S aureus clearance in vivo (p = 0.008) with a 2.6-fold decrease in bacterial bioburden on Day 7 postimplantation.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Choe

Narayanan

Gandhi

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…In line with this, it has been shown that several IDRs suppress proinflammatory responses modulating M1eM2 macrophage differentiation (Pena et al, 2013), suppressing potentially harmful excessive inflammatory responses (Scott et al, 2007) and offering protection by enhancing the innate immune defences of the host, thus suggesting again that whey-derived peptides could be used as natural IDRs.…”

Section: Pes-1 Fraction Can Promote Regulatory T Cell Responsesmentioning

confidence: 70%

Immunomodulatory activities of whey β-lactoglobulin tryptic-digested fractions

Rodríguez‐Carrio

Fernández

Riera

2014

International Dairy Journal

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Combating Implant Infections: Shifting Focus from Bacteria to Host

et al. 2020

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commensal skin bacteria, Staphylococci, and in particular Staphylococcus aureus, have a strong tendency to colonize foreign bodies and cause IAI. [3,4] Important for the underlying pathophysiology, Staphylococci are highly competent at producing biofilms on implant surfaces, which encapsulate the bacterial niche from the outside environment, [5,6] thereby protecting the bacteria from host defense systems and antibiotics. [7] Antibiotics are administered as a routine procedure. [8] However, as a consequence of widespread antibiotics usage, bacteria are exposed to subinhibitory concentrations of antibiotics at a larger scale, driving their development toward antibiotic resistance, [9] as illustrated by the emergence of methicillin-resistant S. aureus (MRSA). [10,11] As an improvement over current clinically applied local antibiotics delivery systems, [12] the recent developments in implant surface engineering approaches allow better antimicrobial functionalities to be incorporated to allow for more tunable and controlled drug release. [13-15] The "race to the surface" model is popular among biomaterials researchers to predict the biomaterials fate, resulting from the competition between eukaryotic cells and bacteria at the material surface. [16] Using this template, implant antibacterial properties are being stemmed from direct contact killing mechanisms due to implant surface modifications [17,18] or firm immobilization of drugs, [19,20] as they both "shield" the implant from bacterial adhesion. The current anti-infective biomaterials strategies being explored can be categorized as: 1) implant functionalization with antibiotics or antibacterial drugs such as host defense peptides (HDPs), inorganic materials (e.g., chitosan and derivatives), and inorganics (e.g., silver, copper, and zinc metal nanoparticles (NPs)), 2) anti-biofilm surface modification (e.g., coating with antifouling polymers or quorum sensor inhibitors), or 3) physical surface changes for direct contact-killing properties (e.g., nanotubes, nanopillars, and metal implantation). [15,21] Emerging as a serious alternative or adjuvant therapy to antibiotics, bacteriophage (phage) therapy uses viruses responsible for the lysis of specific bacterial strains. [22,23] As a natural predator of bacteria, phages employ different killing mechanisms, making multidrug resistant bacteria susceptible for phages. [24] Moreover, phages are highly specific for pathogenic cells, which can eliminate disastrous off-target effects in the host. [25] As a limitation, the use of phage cocktails is needed for therapeutic efficacy, [26] while there is currently is no conclusive data on possible long-term side effects of phage therapy in The widespread use of biomaterials to support or replace body parts is increasingly threatened by the risk of implant-associated infections. In the quest for finding novel anti-infective biomaterials, there generally has been a one-sided focus on biomaterials with direct antibacterial properties, which leads to excessive use of antibacterial ag...

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Synthetic Cationic Peptide IDR-1018 Modulates Human Macrophage Differentiation

Cited by 81 publications

References 47 publications

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration

Immunomodulatory activities of whey β-lactoglobulin tryptic-digested fractions

Combating Implant Infections: Shifting Focus from Bacteria to Host

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