Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application

Nell, Marja J.; Tjabringa, G. Sandra; Wafelman, Amon R.; Verrijk, R.; Hiemstra, Pieter S.; Drijfhout, Jan W.; Grote, J. J.

doi:10.1016/j.peptides.2005.09.016

Cited by 162 publications

(165 citation statements)

References 44 publications

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“…1E). This finding is in agreement with several studies showing inactivation of the antibacterial function of LL-37 by LPS (35)(36)(37)(38)(39). It is interesting to note that the elastic modulus of A549 cells treated with a premixed solution of LPS and LL-37 is significantly lower than the elastic modulus of cells treated with either agonist separately.…”

Section: Ll-37 Increases the Stiffness Of A549 And Primary Human Lungsupporting

confidence: 92%

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Byfield

Kowalski

Cruz

et al. 2011

The Journal of Immunology

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In addition to its antibacterial activity, the cathelicidin-derived LL-37 peptide induces multiple immunomodulatory effects on host cells. Atomic force microscopy, F-actin staining with phalloidin, passage of FITC-conjugated dextran through a monolayer of lung epithelial cells, and assessment of bacterial outgrowth from cells subjected to Pseudomonas aeruginosa infection were used to determine LL-37’s effect on epithelial cell mechanical properties, permeability, and bacteria uptake. A concentration-dependent increase in stiffness and F-actin content in the cortical region of A549 cells and primary human lung epithelial cells was observed after treatment with LL-37 (0.5–5 μM), sphingosine 1-phosphate (1 μM), or LPS (1 μg/ml) or infection with PAO1 bacteria. Other cationic peptides, such as RK-31, KR-20, or WLBU2, and the antibacterial cationic steroid CSA-13 did not reproduce the effect of LL-37. A549 cell pretreatment with WRW4, an antagonist of the transmembrane formyl peptide receptor-like 1 protein attenuated LL-37’s ability to increase cell stiffness. The LL-37–mediated increase in cell stiffness was accompanied by a decrease in permeability and P. aeruginosa uptake by a confluent monolayer of polarized normal human bronchial epithelial cells. These results suggested that the antibacterial effect of LL-37 involves an LL-37–dependent increase in cell stiffness that prevents epithelial invasion by bacteria.

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Section: Ll-37 Increases the Stiffness Of A549 And Primary Human Lungsupporting

confidence: 92%

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Byfield

Kowalski

Cruz

et al. 2011

The Journal of Immunology

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“…Actually, it is in the more physiological conditions when LL-37 exhibits a wide range of immunomodulatory properties in vitro and these activities can be recapitulated in animal models [76]. A 24-amino acid-shortened derivative of the 37-mer LL-37 shows LPS and lipoteichoic acid neutralization activities similar to the mother peptide but induces lower levels of pro-inflammatory effects [77]. LL-37 was widely studied and showed to have multiple immunomodulatory activities, including activation of macrophages, upregulation chemokines and chemokine receptor production, and promotion of wound healing [76].…”

Section: Human Cathelicidinsmentioning

confidence: 99%

Immunomodulatory effects of anti-microbial peptides

Ötvös¹

2016

Acta Microbiologica et Immunologica Hungarica

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Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro-and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

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“…Human LL-37, control scrambled peptide (LG-37), as well as the set of 16 overlapping 22mer peptides covering the complete amino acid sequence of LL-37 were prepared by solid phase synthesis on an automated peptide synthesizer (SyroII, Multisyntech, Witten, Germany) as decribed (31). The sequences of the various peptides are summarized in Table I.…”

Section: Ll-37 and Derived Peptidesmentioning

confidence: 99%

LL-37 Directs Macrophage Differentiation toward Macrophages with a Proinflammatory Signature

Does

Beekhuizen

Ravensbergen

et al. 2010

The Journal of Immunology

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The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MΦ-2; driven by M-CSF) versus proinflammatory macrophages (MΦ-1; driven by GM-CSF) as well as on fully differentiated MΦ-1 and MΦ-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 μg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF–driven macrophage differentiation. Exposure of fully differentiated MΦ-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MΦ-2. In contrast, LL-37 had no effect on fully differentiated MΦ-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

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Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application

Abstract: in terms of LPS and LTA neutralization and lower pro-inflammatory activity. In addition, the acetylated and amidated version of this peptide shows no toxicity and displays higher or equal antimicrobial activity compared to LL-37.

Cited by 162 publications

References 44 publications

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Cathelicidin LL-37 Increases Lung Epithelial Cell Stiffness, Decreases Transepithelial Permeability, and Prevents Epithelial Invasion by Pseudomonas aeruginosa

Immunomodulatory effects of anti-microbial peptides

LL-37 Directs Macrophage Differentiation toward Macrophages with a Proinflammatory Signature

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