The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes.
LL-37 is a cationic host defense peptide that is highly expressed during acute inflammation and that kills bacteria by poorly defined mechanisms, resulting in permeabilization of microbial membranes. High concentrations of LL-37 have also been reported to have cytotoxic effects against eukaryotic cells, but the peptide is clearly capable of differentiating between membranes with different compositions (eukaryotic versus bacterial membranes). Eukaryotic cells such as leukocytes change their membrane composition during apoptotic cell death, when they are turned into nonfunctional but structurally intact entities. We tested whether LL-37 exerted specific activity on apoptotic cells and found that the peptide selectively permeabilized the membranes of apoptotic human leukocytes, leaving viable cells unaffected. This activity was seemingly analogous to the direct microbicidal effect of LL-37, in that it was rapid, independent of known surface receptors and/or active cell signaling, and inhibitable by serum components such as high-density lipoprotein. A similar selective permeabilization of apoptotic cells was recorded for both NK cells and neutrophils. In the latter cell type, LL-37 permeabilized both the plasma and granule membranes, resulting in the release of both lactate dehydrogenase and myeloperoxidase. Apoptosis is a way for inflammatory cells to die silently and minimize collateral tissue damage by retaining tissue-damaging and proinflammatory substances within intact membranes. Permeabilization of apoptotic leukocytes by LL-37, accompanied by the leakage of cytoplasmic as well as intragranular molecules, may thus shift the balance between pro- and anti-inflammatory signals and in this way be of importance for the termination of acute inflammation.
Björstad
Ase
A
Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden. ase.bjorstad@rheuma.gu.se
Askarieh
Galia
G
Brown
Kelly L
KL
Christenson
Karin
K
Forsman
Huamei
H
Onnheim
Karin
K
Li
Hsin-Ni
HN
Teneberg
Susann
S
Maier
Olaf
O
Hoekstra
Dick
D
Dahlgren
Claes
C
Davidson
Donald J
DJ
Bylund
Johan
J
D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010539:Permeability; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D016877:Oxidants; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D054804:Cathelicidins