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JAC Advance Access originally published online on December 30, 2005
Journal of Antimicrobial Chemotherapy 2006 57(2):260-265; doi:10.1093/jac/dki460
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids

W. Baranska-Rybak1,2,*,{dagger}, A. Sonesson2,{dagger}, R. Nowicki1 and A. Schmidtchen2,*

1 Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Debinki 7 Street, 80-288 Gdansk, Poland; 2 Dermatology and Venereology, Department of Clinical Sciences, Biomedical Center B14, Tornavägen 10, S-22184 Lund, Sweden

* Corresponding authors. E-mail: wbaranska{at}pf.pl or artur.schmidtchen{at}med.lu.se

Received 2 March 2005; returned 19 May 2005; revised 19 October 2005; accepted 26 November 2005


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Objectives: The antibacterial activity of antimicrobial peptides is influenced by various factors such as salt content, pH and the presence of proteins. In this study, we explored the antibacterial action of the human cathelicidin LL-37 in physiologically relevant conditions, i.e. various human wound fluids, human plasma fractions and serum.

Methods: Radial diffusion assays using Staphylococcus aureus and Escherichia coli were employed for the study of antibacterial effects of LL-37 in the presence of 12 different wound fluids, citrate-, heparin- or EDTA-plasma, or human serum. Glycosaminoglycan content of wound fluids was determined by an Alcian Blue-binding assay. Protein content of wound fluids was measured by the Bradford method. A slot-binding assay was used to study the effects of inhibitors on the interaction between LL-37 and glycosaminoglycans.

Results: Five of twelve wound fluids derived from acute wounds showed marked inhibitory effects on the antibacterial action of LL-37. The inhibition was significantly correlated with high glycosaminoglycan content in wound fluid. Analogous to these findings, heparin-plasma strongly inhibited the antibacterial effect of LL-37. The interaction between LL-37 and glycosaminoglycans was abrogated by the cationic polymers DEAE-dextran and chitosan, yielding increased activity of LL-37.

Conclusions: Glycosaminoglycan-rich biological fluids inhibit the antibacterial effects of LL-37. Furthermore, polycations that bind to glycosaminoglycans increase the antibacterial activities of endogenous antimicrobial peptides in glycosaminoglycan-containing biological fluids.

Keywords: antibacterial peptides , serum , plasma , wound fluids , bacteria


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Antimicrobial peptides play pivotal roles in cutaneous defences against various microbes. In humans, the cathelicidin hCAP-18 is processed by proteinase 3 to generate the active peptide LL-37, which exerts antibacterial activity.1 LL-37 has been isolated from neutrophils2 and subpopulations of lymphocytes and monocytes.3 The peptide is also found in seminal plasma,4 in the lung,5 and in keratinocytes during inflammation.6 The significance of cathelicidins for bacterial clearance is exemplified by recent findings indicating that the mouse antibacterial peptide CRAMP protects the skin from invasive bacterial infection.7 The antimicrobial action of LL-37 is inhibited by apolipoprotein A-1, other factors in human plasma,8 serum and is influenced by pH and ion composition.9 Work in our laboratory has demonstrated that LL-37 binds to glycosaminoglycans (GAGs), such as dermatan sulphate (DS) and heparin, and that this binding blocks the bactericidal effect of the peptide.10,11 Notably, GAGs occur in wound fluid (WF) in significant concentrations.12 Thus, considering the heterogeneity of biological fluids, as well as the type of plasma fractions used in various in vitro experiments (such as citrate-, heparin- or EDTA-plasma), it may be expected that LL-37 is differently affected in these environments. Here, we address this question and show that plasma fractions and WFs variably affect the antibacterial action of LL-37, and that the inhibition is most pronounced in GAG-rich WFs and in heparin-plasma.


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Bacterial isolates

Staphylococcus aureus and Escherichia coli clinical isolates were obtained from patients with skin infections. S. aureus molecular typing was performed using ADSRRS-fingerprinting analysis.13 Briefly, S. aureus DNA was digested with the two restriction enzymes BamHI (10 U/µL) (Sigma) and XbaI (10 U/µL) (Sigma). Cohesive ends of DNA were ligated with adapters and amplified. PCR products were electrophoresed on polyacrylamide gels, stained with ethidium bromide and photographed under UV-light. The three S. aureus strains used in the study represent the individual genotypes L, W and O.13 E. coli ATCC 25922 and S. aureus ATCC 29213 isolates were provided by the Clinical Bacteriology Unit at Lund University Hospital.

Radial diffusion assay

Radial diffusion assays (RDAs) were performed as previously described.11,14 The underlay gel [0.03% (w/v) TSB/1% (w/v) low electroendosmosis type (low-EEO) agarose (Sigma, St Louis, MO, USA)/0.02% Tween 20] was poured into a 85 mm diameter Petri dish. After the agarose solidified, 4 mm diameter wells were punched and 6 µL of test sample comprising 50 or 100 µM LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES; MW 4492) diluted in citrate-, EDTA- or heparin-plasma, serum (50 or 96%) or WFs (50%) was added to each well. WFs 1 to 12 were obtained from surgical drainages following mastectomy as previously described.10 All fluids were stored at –20°C. The use of this material was approved by the Ethics Committee at Lund University (LU 708-01). Plates were incubated at 37°C for 3 h to allow diffusion of the peptides. The underlay gel was then covered with 5 mL of molten overlay (6% TSB and 1% low-EEO agarose in dH2O). Antimicrobial activity of a peptide was visualized as a clear zone around each well after 18–24 h of incubation at 37°C.

Glycosaminoglycan assay

Alcian Blue-binding assay was performed according to the manufacturer's instructions (Wieslab, Lund).15 Briefly, WFs as well as chondroitin sulphate-6 (12, 5, 25, 50, 100, 200 and 400 mg/L) (for the standard curve) were mixed with 8 M GuHCl and incubated at room temperature (RT) for 15 min. This was followed by addition of SAT solution (0.3% sulphuric acid/0.75% Triton X-100), incubation and addition of the Alcian Blue solution. After incubation for 15 min at RT, samples were centrifuged and pellets washed with DMSO solution (40% dimethyl sulphoxide/0.05 M MgCl2) and dissolved in Gu-Prop solution (4 M guanidine-HCl/33% 1-propanol/0.25% Triton X-100) before reading absorbance at 600 nm.

Protein content assay

The protein concentration of the WFs was determined using a Bradford assay.16 The tested samples were diluted in 10 mM Tris, pH 7.4 to 100 µL, mixed with Bradford solution and incubated at RT for 15 min before absorbance measurement at 595 nm.

Slot binding assay

This was performed essentially as previously described.17 LL-37 was applied onto nitrocellulose membranes (Hybond, Amersham). Membranes were blocked (PBS, pH 7.4/0.25% Tween 20/3% bovine serum albumin) for 1 h and incubated with radiolabelled DS (~10 mg/L) for 1 h in the same buffer. Unlabelled polysaccharides were added for competition of binding. The membranes were washed (3 x 10 min) (PBS, pH 7.4/0.25% Tween 20). A Bas 2000 radioimaging system (Fuji) was used for visualization of radioactivity.

Statistical analyses

Statistical analysis of the relation between WF GAG content and inhibition of LL-37 was performed using the Mann–Whitney Rank Sum Test, and differences were considered significant at P < 0.05. The Spearman Rank Order Correlation Test was used to determine the presence of correlation between protein and GAG content in the WFs, or the ability to inhibit LL-37.


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Glycosaminoglycans in acute wound fluids affect the antibacterial action of LL-37

The effect of human WFs on the antibacterial activity of LL-37 was investigated. Using RDA, LL-37 was tested against S. aureus in the presence of 12 different WFs collected from patients post-surgery. A variable inhibition of the antibacterial effect of LL-37 was noted (Table 1). LL-37 was not degraded when incubated with the acute WFs overnight at 37°C (not shown), consistent with our previous data demonstrating that LL-37 is not degraded by non-infected WFs.10


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  		Table 1.. Antibacterial effects of LL-37 in the presence of WFs

 
Next, we determined whether the inhibition correlated with the protein or GAG content of the WFs. The protein content of the 12 WFs ranged from 34 to 60 g/L (Table 1), which corresponded well with previous investigations.18 No correlation between the protein content and the ability to inhibit LL-37 in RDA was found (Figure 1a). Previous studies showed that GAGs of various types (DS, heparan sulphate) inhibit the antibacterial action of LL-37. Thus, the GAG content of the WFs was determined and ranged between 0 and 48 mg/L, in line with previous measurements.12 No correlation between GAG and protein content was detected (Figure 1b). However, a statistically significant correlation between GAG content of the WFs and LL-37 inhibition was found (Figure 1c). WFs containing high amounts of GAGs (20–48 mg/L) strongly inhibited the activity of 100 µM LL-37 against the three S. aureus isolates (genotypes O, L and W). Dose response experiments using S. aureus (genotype L), as well as S. aureus ATCC 29213 and E. coli ATCC 25922 strains, corroborated this finding (Figure 2a). It was noted that a lower concentration of LL-37 was required for inhibition of the E. coli strain.


Figure 1
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  		Figure 1.. (a) Protein content of WFs versus antibacterial zones after addition of LL-37 to the different WFs. The protein concentration (x-axis) is plotted against the antibacterial zone (y-axis, in mm). No correlation between antibacterial activity and protein concentration was detected using three clinical isolates of S. aureus (S. a. 1-3). (b) Relationship between GAGs and protein content. No significant correlation between GAG (y-axis) and protein content (x-axis) was found. (c) GAG content (x-axis) is plotted against the resulting antibacterial zones (y-axis). WFs were separated into two groups, those yielding complete or almost complete inhibition, and those yielding little or partial inhibition of 100 µM LL-37 in the RDA. A statistically significant correlation between GAG content and inhibition of LL-37-mediated bacterial killing was demonstrated for the two groups (P < 0.01).

 

Figure 2
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  		Figure 2.. (a) Antimicrobial activity of LL-37 against S. aureus (genotype L) (left panel), S. aureus ATCC 29213 (central panel) and E. coli ATCC 25922 (right panel) in the presence of WFs (WF6, 0 mg GAG/L: filled circles; WF3, 44 mg GAG/L: open circles). (b) The cationic polysaccharide chitosan blocks the GAG–LL-37 interaction in a slot binding experiment. LL-37 was applied onto nitrocellulose filters, which were incubated with iodinated DS (~10 mg/L) followed by autoradiography. Chitosan at the indicated concentrations was added for competition of binding. C, control (no chitosan added). (c) Activity of LL-37 against S. aureus (genotype L) (left panel), S. aureus ATCC 29213 (central panel) and E. coli ATCC 25922 (right panel) in the presence of WF3 (44 mg of GAG/L) (open circles), WF3 with 0.5 µg of chitosan (filled triangles) or WF3 with 0.5 µg of DEAE-dextran (filled circles). The resulting antibacterial zones in RDA are presented. All values are means ± SEM (n = 3).

 
Polycations bind to DS and enhance the effect of LL-37 in wound fluids

Considering that GAGs bind to and inhibit LL-37, we speculated that other polycations might inhibit this interaction. Thus, in a previously established slot-binding assay,10 the effects of the cationic polymer chitosan were studied. As assessed by the slot-binding experiment, LL-37 bound to DS in physiological salt conditions (Figure 2b), and addition of the polycation chitosan at or above 1 mg/L blocked the binding of radiolabelled DS to LL-37 (Figure 2b). The polycation DEAE-dextran yielded similar results (not shown). Next, we examined whether chitosan and DEAE-dextran, by blocking the GAG–LL-37 interaction, could enhance the antibacterial effect of LL-37 against S. aureus and E. coli in the presence of GAG-rich WF. Thus, LL-37 was added to WF (containing ~0.15 µg of GAG) and analysed by RDA in the absence or presence of 0.5 µg of chitosan or DEAE-dextran. Both polycations enhanced the antibacterial activity of LL-37 against the two S. aureus isolates (genotype L and ATCC 29213) (Figure 2c). Increased activity of LL-37 against E. coli ATCC 25922 was observed after addition of DEAE-dextran to the GAG-rich WF (Figure 2c). Under the same conditions, 0.5 µg of DEAE-dextran or chitosan alone did not yield any antibacterial zones in RDA.

Antibacterial effects of LL-37 in plasma fractions and serum

LL-37-mediated killing of the clinical S. aureus and E. coli isolates was not significantly affected by the presence of 50% serum, citrate-plasma or EDTA-plasma (Figure 3a). However, heparin-plasma markedly inhibited the antibacterial effects of LL-37 (Figure 3a). In general, S. aureus was less sensitive to LL-37 in the absence or presence of serum and plasma. Using 100 µM LL-37, addition of 96% serum and plasma to the three S. aureus isolates yielded minor or no inhibitory zones in RDA (not shown). Thus, for illustration of the effects of serum and plasma addition (at 96%), results with the clinical E. coli isolate as well as E. coli ATCC 25922 are presented (Figure 3b). Fluids without LL-37 did not yield any inhibitory zones against the bacterial isolates studied herein (not shown).


Figure 3
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  		Figure 3.. Activity of LL-37 against E. coli and S. aureus in the presence of human serum and plasma. (a) Addition of plasma fractions and serum (at 50%) to LL-37 and analysis by RDA. The x-axis shows S. aureus isolates 1–3 and E. coli. The y-axis shows the diameter of the antibacterial zone (in mm) in the RDA and the z-axis indicates the plasma fractions, serum or buffer (in 10 mM Tris, pH 7.4) in combination with LL-37 (50 and 100 µM). (b) Illustration of activity of LL-37 (at 100 µM) in RDA against two E. coli strains in the presence of plasma, serum or buffer (all at 96%). C-plasma, citrate-plasma; H-plasma, heparin-plasma.

 

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LL-37 displays multiple and sequential interactions with bacterial surface components, such as lipopolysaccharide, teichoic acid, peptidoglycans and at the plasma membrane, phospholipid groups. Electrostatic interactions with anisotropic membrane environments promote conformational changes of the peptide, which in turn facilitate hydrophobic membrane interactions, oligomerization and, finally, membrane destabilization and bacterial inactivation. Clearly, these complex interactions are affected by various components that interact with LL-37. The main and novel finding in this report is that WFs containing high levels of GAGs markedly inhibit the antibacterial action of LL-37. From a structural point of view, spacing of basic amino acids in LL-37 facilitates formation of ion pairs with spatially defined sulpho- or carboxyl groups in GAGs present in WF (heparin/heparan sulphate or DS). Furthermore, N-acetyl and hydroxyl groups in GAGs require ‘matching’ residues in LL-37, such as leucine and glutamine or asparagine, enabling hydrophobic interactions and hydrogen bonding, respectively.19 Thus, these specific peptide–GAG interactions, resulting in competition for bacterial binding, explain the abrogated antibacterial activity of LL-37 in GAG-rich WFs in vitro.

From a biological perspective, our data imply that differences in GAG levels may affect the antimicrobial effects of LL-37 during wound healing in vivo. Hypothetically, the high inflammatory and proteolytic activity of chronic leg ulcers20 could lead to the release of GAGs derived from the connective tissues, thus inhibiting endogenous antimicrobial peptides, such as LL-37. This view is compatible with the finding that chronic ulcers are colonized and infected by various Gram-negative and Gram-positive bacteria.21 In this context, it is highly interesting that bacteria, such as Pseudomonas aeruginosa, are able to release GAGs from connective tissues and hence block the bactericidal actions of LL-37.17,22 Hypothetically, considering the herein-noted variation of wound fluid GAG levels, high GAG concentrations in wound tissues could predispose to bacterial colonization and infection. If so, antibacterial or protease-blocking therapies could lead to enhancement of antibacterial activities of LL-37, as well as other antimicrobial peptides, during wound healing in vivo. Clearly, these mechanisms need further investigation in future clinically-orientated studies.

From an experimental perspective, the finding that GAG-rich WFs, as well as heparin-plasma, block the antibacterial effect of LL-37, indicates that experimental conditions must be highly standardized in antimicrobial assays using physiological fluids. Finally, our finding that cationic polymers may block the interaction between LL-37 and GAGs provides a logical rationale for the use of various polycations in the development of novel antimicrobial therapies based on enhancement of endogenous peptide activity.


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No declarations were made by the authors of this paper.


   Footnotes
 
{dagger} Dr Baranska-Rybak and Dr Sonesson contributed equally to this work. Back


   Acknowledgements
 
This work was supported by grants from the Swedish Research Council (project 13471), the Royal Physiographic Society in Lund, the Welander-Finsen, Söderbergs, Crafoord, Österlund, Lundgrens, Lions and Kock Foundations, and The Swedish Government Support for Clinical Research (ALF). Dr W. B.-R. was supported by a grant from the Swedish Institute.


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1. Sörensen OE, Follin P, Johnsen AH et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 2001; 97: 3951–9.[Abstract/Free Full Text]

2. Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol 2004; 75: 39–48.[Abstract/Free Full Text]

3. Agerberth B, Charo J, Werr J et al. The human antimicrobial and chemotactic peptides LL-37 and {alpha}-defensins are expressed by specific lymphocyte and monocyte populations. Blood 2000; 96: 3086–93.[Abstract/Free Full Text]

4. Malm J, Sörensen O, Persson T et al. The human cationic antimicrobial protein (hCAP-18) is expressed in the epithelium of human epididymis, is present in seminal plasma at high concentrations, and is attached to spermatozoa. Infect Immun 2000; 68: 4297–302.[Abstract/Free Full Text]

5. Bals R, Wang X, Wu Z et al. Human ß-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 1998; 102: 874–80.[Web of Science][Medline]

6. Frohm M, Agerberth B, Ahangari G et al. The expression of the gene coding for antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 1997; 24: 15258–63.

7. Nizet V, Ohtake T, Lauth X et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001; 414: 454–7.[CrossRef][Medline]

8. Wang Y, Agerberth B, Lothgren A et al. Apolipoprotein A-I binds and inhibits antibacterial/cytotoxic peptide LL-37. J Biol Chem 1998; 273: 33115–8.[Abstract/Free Full Text]

9. Johansson J, Gudmundsson GH, Rottenberg ME et al. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J Biol Chem 1998; 273: 3718–24.[Abstract/Free Full Text]

10. Schmidtchen A, Frick IM, Andersson E et al. Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Mol Microbiol 2002; 46: 157–68.[CrossRef][Web of Science][Medline]

11. Andersson E, Rydengård V, Sonesson A et al. Antimicrobial activities of heparin-binding peptides. Eur J Biochem 2004; 271: 1219–26.[Medline]

12. Penc SF, Pomahac B, Winkler T et al. Dermatan sulphate released after injury is a potent promoter of fibroblast growth factor-2 function. J Biol Chem 1998; 273: 28116–21.[Abstract/Free Full Text]

13. Masny A, Plucienniczak A. Fingerprinting of bacterial genomes by amplification of DNA fragments surrounding rare restriction sites. BioTechniques 2001; 31: 930–36.[Web of Science][Medline]

14. Lehrer RI, Rosenman M, Harwig SS et al. Ultrasensitive assays for endogenous antimicrobial polypeptides. J Immunol Methods 1991; 137: 167–73.[CrossRef][Web of Science][Medline]

15. Björnsson S. Quantitation of proteoglycans as glycosaminoglycans in biological fluids using an alcian blue dot blot analysis. Anal Biochem 1998; 256: 229–37.[CrossRef][Web of Science][Medline]

16. Berlau J, Lorenz P, Beck R et al. Analysis of aqueous humour proteins of eyes with and without pseudoexfoliation syndrome. Graefes Arch Clin Exp Opthalmol 2001; 239: 743–6.[Medline]

17. Schmidtchen A, Frick IM, Björck L. Dermatan sulphate is released by proteinases of common pathogenic bacteria and inactivates antibacterial {alpha}-defensin. Mol Microbiol 2001; 39: 708–13.[CrossRef][Web of Science][Medline]

18. Schmidtchen A. Chronic ulcers: a method for sampling and analysis of wound fluid. Acta Derm Venereol 1999; 79: 291–295.[CrossRef][Medline]

19. Capila I, Linhardt RJ. Heparin-protein interactions. Angew Chem Int Ed Engl 2002; 41: 390–412.[CrossRef]

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21. Davies CE, Wilson MJ, Hill KE et al. Use of molecular techniques to study microbial diversity in the skin: chronic wounds reevaluated. Wound Repair Regen 2001; 9: 332–40.[CrossRef][Web of Science][Medline]

22. Schmidtchen A, Holst E, Tapper H et al. Elastase-producing Pseudomonas aeruginosa degrade plasma proteins and extracellular products of human skin and fibroblasts, and inhibit fibroblast growth. Microb Pathogen 2003; 34: 47–55.[CrossRef][Web of Science][Medline]


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