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Disruption of the nuclear membrane by the antimicrobial peptide LL‐37 leads to the formation of neutrophil extracellular traps (793.1)
Author(s) -
Neumann Ariane,
Völlger Lena,
Nerlich Andreas,
Meerloo Timo,
Gallo Richard,
Nizet Victor,
Naim Hassan,
KöckritzBlickwede Maren
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.793.1
Subject(s) - neutrophil extracellular traps , cathelicidin , microbiology and biotechnology , innate immune system , peptide , antimicrobial peptides , membrane , extracellular , sphingomyelin , chemistry , nuclear membrane , inner membrane , confocal microscopy , immunofluorescence , biophysics , biology , biochemistry , inflammation , immunology , receptor , antibody
Neutrophil extracellular traps (NETs) have been described as a fundamental innate immune defense mechanism. During formation of NETs the nuclear membrane of mammalian cells is disrupted by a yet unknown mechanism. The cathelicidin LL‐37 has been shown to bind and damage membranes deficient in cholesterol and sphingomyelin such as bacterial membranes. Consequently, we hypothesized that LL‐37 could potentially damage the nuclear membrane, which contains reduced amounts of cholesterol, and thereby facilitates the formation of NETs by activated neutrophils. Different concentrations of LL‐37 were used to stimulate primary blood‐derived neutrophils. The percentage of NET‐releasing cells was calculated using immunofluorescence microscopy and revealed that LL‐37 is able to facilitate NET‐formation. Cells treated with LL‐37 showed a clear disruption of the nuclear membrane by electron microscopy and confocal immunofluorescence microscopy. Accordingly, when blocking the cleavage and subsequent activation of endogenous LL‐37, NET formation was significantly diminished. Biochemical assays utilizing a random LL‐37‐fragment library indicated that the NET‐induction is mediated by the hydrophobic character of the peptide. In conclusion, this study demonstrates a novel role of the antimicrobial peptide LL‐37 in host immune defence: the disruption of the nuclear membrane and subsequent formation of NETs. Grant Funding Source : German Research Council (DFG)