The Anti-Microbial Peptide (Lin-SB056-1)2-K Reduces Pro-Inflammatory Cytokine Release through Interaction with Pseudomonas aeruginosa Lipopolysaccharide.

Lucia Grassi,Giuseppantonio Maisetta,Andrea C Rinaldi,Giovanna Batoni,Arianna Pompilio,Semih Esin,Esingül Kaya,Aurélie Crabbé,Giovanni Di Bonaventura,Enrico Sanjust

doi:10.3390/antibiotics9090585

Lucia Grassi, Giuseppantonio Maisetta + Show 8 more

Open Access

https://doi.org/10.3390/antibiotics9090585

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Abstract

The ability of many anti-microbial peptides (AMPs) to modulate the host immune response has highlighted their possible therapeutic use to reduce uncontrolled inflammation during chronic infections. In the present study, we examined the anti-inflammatory potential of the semi-synthetic peptide lin-SB056-1 and its dendrimeric derivative (lin-SB056-1)2-K, which were previously found to have anti-microbial activity against Pseudomonas aeruginosa in in vivo-like models mimicking the challenging environment of chronically infected lungs (i.e., artificial sputum medium and 3-D lung mucosa model). The dendrimeric derivative exerted a stronger anti-inflammatory activity than its monomeric counterpart towards lung epithelial- and macrophage-cell lines stimulated with P. aeruginosa lipopolysaccharide (LPS), based on a marked decrease (up to 80%) in the LPS-induced production of different pro-inflammatory cytokines (i.e., IL-1β, IL-6 and IL-8). Accordingly, (lin-SB056-1)2-K exhibited a stronger LPS-binding affinity than its monomeric counterpart, thereby suggesting a role of peptide/LPS neutralizing interactions in the observed anti-inflammatory effect. Along with the anti-bacterial and anti-biofilm properties, the anti-inflammatory activity of (lin-SB056-1)2-K broadens its therapeutic potential in the context of chronic (biofilm-associated) infections.

Highlights

Anti-microbial peptides (AMPs) represent a key component of the innate immune system of many multicellular organisms, playing a major role in the first line of defense against a broad range of pathogens [1,2]
In order to determine the anti-inflammatory potential of lin-SB056-1 and its dendrimeric derivative2 -K, we evaluated the effect of both peptides on the production of pro-inflammatory cytokines by lung epithelial cells (A549 cell line) and macrophage-like cells (i.e., THP-1 cells differentiated with 12-O-tetradecanoylphorbol-13-acetate, TPA) in response to P. aeruginosa LPS
Previous studies of our group focused on the evaluation of the anti-microbial properties of the semi-synthetic peptide lin-SB056-1, with particular attention to the development of strategies to improve its therapeutic potential against P. aeruginosa lung infections [17,18,19]

Summary

Introduction

Anti-microbial peptides (AMPs) represent a key component of the innate immune system of many multicellular organisms, playing a major role in the first line of defense against a broad range of pathogens [1,2]. In addition to the direct anti-microbial activity, many peptides have been found to exhibit multifaceted immunomodulatory properties at sub-inhibitory concentrations, including activation of controlled inflammatory responses, regulation of chemotaxis, modulation of cell differentiation, stimulation of angiogenesis and enhancement of wound healing [4,5]. All these activities contribute to the ability of AMPs to promote pathogen clearance and resolution of the infection, while preventing excessive and potentially harmful pro-inflammatory responses. Due to their dual (anti-bacterial and immunomodulatory) mechanism of action, AMPs are gaining increasing interest for the management of chronic infections [7,8,9,10,11]

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