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Antimicrobial Agents and Chemotherapy, March 2009, p. 1027-1038, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01310-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Host Defense Peptide LL-37 Selectively Permeabilizes Apoptotic Leukocytes{triangledown}

Åse Björstad,1* Galia Askarieh,2 Kelly L. Brown,1 Karin Christenson,1 Huamei Forsman,1 Karin Önnheim,1 Hsin-Ni Li,3 Susann Teneberg,4 Olaf Maier,5 Dick Hoekstra,5 Claes Dahlgren,1 Donald J. Davidson,3 and Johan Bylund1

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden,1 Department of Infectious Diseases, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden,2 MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, Scotland,3 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden,4 Department of Cell Biology, Membrane Cell Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands5

Received 30 September 2008/ Returned for modification 16 October 2008/ Accepted 2 December 2008

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.

* Corresponding author. Mailing address: Department of Rheumatology and Inflammation Research, University of Gothenburg, Guldhedsgatan 10, Gothenburg S-413 46, Sweden. Phone: 46 31 342 46 35. Fax: 46 31 82 88 98. E-mail: ase.bjorstad{at}rheuma.gu.se

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1027-1038, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01310-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, H.-N., Barlow, P. G., Bylund, J., Mackellar, A., Bjorstad, A., Conlon, J., Hiemstra, P. S., Haslett, C., Gray, M., Simpson, A. J., Rossi, A. G., Davidson, D. J. (2009). Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages. J. Leukoc. Biol. 86: 891-902 [Abstract] [Full Text]  


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