The human cationic host defense peptide LL-37 mediates contrasting effects on apoptotic pathways in different primary cells of the innate immune system
Peter G. BarlowYuexin LiThomas S. WilkinsonDawn M. E. BowdishY. Elaine LauCéline CosseauChristopher HaslettA. John SimpsonRobert E. W. HancockDonald J. Davidson
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Abstract The human cathelicidin LL-37 is a cationic host defense peptide (antimicrobial peptide) expressed primarily by neutrophils and epithelial cells. This peptide, up-regulated under conditions of inflammation, has immunomodulatory and antimicrobial functions. We demonstrate that LL-37 is a potent inhibitor of human neutrophil apoptosis, signaling through P2X7 receptors and G-protein-coupled receptors other than the formyl peptide receptor-like-1 molecule. This process involved modulation of Mcl-1 expression, inhibition of BID and procaspase-3 cleavage, and the activation of phosphatidylinositol-3 kinase but not the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. In contrast to the inhibition of neutrophil apoptosis, LL-37 induced apoptosis in primary airway epithelial cells, demonstrating alternate consequences of LL-37-mediated modulation of apoptotic pathways in different human primary cells. We propose that these novel immunomodulatory properties of LL-37 contribute to peptide-mediated enhancement of innate host defenses against acute infection and are of considerable significance in the development of such peptides and their synthetic analogs as potential therapeutics for use against multiple antibiotic-resistant infectious diseases.Keywords:
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One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides. Antimicrobial peptides are classified on the basis of their structure and amino acid motifs. Peptides of the defensin, cathelicidin, and histatin classes are found in humans. In the airways, α-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils. β-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid. Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis. Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation.
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Antimicrobial peptides are the eukaryotic analogues of antibiotics. In addition to their antimicrobial activity, these peptides can signal to host cells and are therefore intermediaries between the innate and adaptive immune systems. Results in a prior study showed that beta-defensins-1 and -2 are made by ocular surface epithelial cells. In the present study, a survey was made of antimicrobial peptide expression, including 17 previously described members of the beta-defensin family, at the surface of the human eye.Total RNA was obtained from 43 fresh and cultured corneal and conjunctival samples, including 9 samples from patients with clinical infections. The expression of 21 antimicrobial peptides was determined using reverse transcription-PCR. Where detected, relative expression was quantitated using real-time PCR.Expression of 7 of the 21 antimicrobial peptides investigated, beta-defensin-1 to -4, liver expressed antimicrobial peptide (LEAP)-1 and -2, and LL37/cathelicidin, were detected frequently in samples of ocular surface epithelia. Distinct but overlapping profiles of expression were detected in cornea and conjunctiva, with expression of beta-defensin-3 and -4 and LEAP1 and -2 most common in cultured corneal epithelia. Expression of beta-defensin-3 was detected in a greater percentage of corneal and conjunctival samples with infection.Together with known lacrimal antimicrobial activities, these results extend the knowledge of antimicrobial activity at an important mucosal site, the ocular surface, allowing synergistic interactions to be investigated. The findings has significant implications both for the understanding of the normal homeostasis of mucosal surfaces and for antimicrobial and anti-inflammatory therapies.
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Antimicrobial peptides are major components of the innate immune defence. They are well conserved along evolution, nontoxic and they ensure potent defences against a large number of pathogens. They act by direct killing of microorganisms and they possess additional roles in the regulation of adaptive immune responses, by recruting or stimulating immune cells. Skin and gut are positioned at the interface of internal milieu and external environment. They represent a physical and chemical barrier against pathogens invasion and the antimicrobial peptides limit pathogen growth in normal conditions. During infection or injury, some of these peptides are overexpressed and disrupt microbial membranes and/or stimulate immune cell recruitment, allowing to return to homeostasis or to increase inflammation. Antimicrobial peptides expression is altered in several diseases: α-defensins deficiency is related with Crohns disease and in skin, cathelicidin LL-37 and β-defensin-2 are overexpressed in psoriasis, while in atopic dermatitis, their expression is decreased. The present review provides an up-to-date summary of the expression and the biological roles of the antimicrobial peptides found in the skin and gastrointestinal mucosa of the host, in normal and pathological conditions. The involvement of these natural antimicrobial peptides in inflammation, is also discussed. Keywords: Innate immunity, antimicrobial peptides, skin, gut, psoriasis, atopic dermatitis, Crohn's disease, inflammation
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ABSTRACT Antimicrobial peptides (AMPs), also known as host defense peptides, are small naturally occurring microbicidal molecules produced by the host innate immune response that function as a first line of defense to kill pathogenic microorganisms by inducing deleterious cell membrane damage. AMPs also possess signaling and chemoattractant activities and can modulate the innate immune response to enhance protective immunity or suppress inflammation. Human pathogens have evolved defense molecules and strategies to counter and survive the AMPs released by host immune cells such as neutrophils and macrophages. Here, we review the various mechanisms used by human bacterial pathogens to resist AMP-mediated killing, including surface charge modification, active efflux, alteration of membrane fluidity, inactivation by proteolytic digestion, and entrapment by surface proteins and polysaccharides. Enhanced understanding of AMP resistance at the molecular level may offer insight into the mechanisms of bacterial pathogenesis and augment the discovery of novel therapeutic targets and drug design for the treatment of recalcitrant multidrug-resistant bacterial infections. Abbreviations: ABC, adenosine triphosphate-binding cassette; AMPs, antimicrobial peptides; l -Ara4N, 4-amino-4-deoxy- l -arabinose; GAC, group A carbohydrate; GAS, group A Streptococcus ; GBS, group B Streptococcus ; GlcNAc, N -acetylglucosamine; HBD 1-6, human β-defensin 1-6; HD 5-6, human α-defensin 5-6; HNP 1-4, human neutrophil peptide 1-4; LL-37, human cathelicidin; LOS, lipooligosaccharide; LPS, lipopolysaccharide; LTA, lipoteichoic acid; mCRAMP, murine cathelicidin-related antimicrobial peptide; MprF, membrane protein multipeptide resistance factor; NETs, neutrophil extracellular traps; pEtN, phosphoethanolamine; PG, phosphatidylglycerol; Sap, sensitive to antimicrobial peptides ABC importer; SK, staphylokinase; TA, teichoic acid; TLR, toll-like receptor; WT, wild-type.
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Saliva is an important biological fluid that reflects human’s health. Its main function is protection of the oral cavity from pathogens. Antimicrobial peptides (AMPs) of the innate immunity may play an important role in anti-infectious defense of the oral cavity, but their relative amount in saliva is low. It’s major component is Proline-rich peptides (PRPs), whose impact in antimicrobial protection remains poorly understood. We suggest that salivary PRPs may reveal their defensive functions upon interaction with other molecules, in particular with AMPs. The aim of this work is an investigation of the combined antibacterial action of salivary PRPs (fragments of Basic salivary proline-rich protein 1: P-H (37-51), IB6 (98-116), p1932) with antimicrobial peptides (histatin 5 and cathelicidin LL-37 and beta-defensin hBD3). Listed PRPs have been obtained by chemical solid-phase synthesis. The method of broth microdilutions was used to compare minimal inhibitory concentrations (MICs) of individual fractions of AMPs and their MICs in the presence of salivary peptides. It was found that in the presence of peptides IB6 (98-116) or P-H (37-51) the activity of defensin hBD3 was increased (reduction of MICs by 2 times) against Staphylococcus aureus SG511. In the presence of IB6 (98-116) or p1932 the activity of this defensin against E. coli ML35p was also improved (MICs of hBD3 was lowered by 2 times). For other combinations of the peptides, this effect was not observed. The obtained data confirm the assumption that the combined action of varied salivary peptides, including cationic Proline-rich peptides, plays an important role in anti-infectious protection of the oral cavity.
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The oral cavity is a warm and moist environment, suitable for microorganisms to colonize and live in harmony as a community, socalled biofilm. In this environment, antimicrobial peptides may play a critical role in maintaining normal oral health and controlling innate and acquired immune systems in response to continuous microbial challenges in periodontal disease. Two major families of antimicrobial peptides, found in the oral cavity, are defensin and cathelicidin. Members of the defensin family are cysteine-rich peptides, synthesized by plants, insects, and mammals. In the oral cavity, four alpha-defensins are synthesized and stored in neutrophil granules, which are converted into active peptides by proteolytic processing, while three human betadefensins (hBDs), hBD-1, hBD-2, and hBD-3, are predominantly produced by oral epithelial cells. The only member of the cathelicidin family found in humans is LL-37, which contains 37 amino acids and begins with two leucines at its N-terminus. Clinically, differential expression of antimicrobial peptides has been reported in different types of periodontal disease, and their presence has been shown in saliva and gingival crevicular fluid. In the first part of our review article, basic knowledge of antimicrobial peptides will be discussed in detail.
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