Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0209050 on July 6, 2009

Published online before print July 6, 2009
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(Journal of Leukocyte Biology. 2009;86:891-902.)
© 2009 The Author(s)

Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages

Hsin-Ni Li*, Peter G. Barlow*, Johan Bylund{dagger}, Annie Mackellar*, Åse Björstad{dagger}, James Conlon*, Pieter S. Hiemstra{ddagger}, Chris Haslett*, Mohini Gray*, A. John Simpson*, Adriano G. Rossi* and Donald J. Davidson*,1

* MRC/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, Scotland;
{dagger} Rheumatology Department, University of Gothenburg, Sweden; and
{ddagger} Department of Pulmonology, Leiden University Medical Center, The Netherlands

1. Correspondence: MRC/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, W2.05, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland. E-mail: donald.davidson{at}ed.ac.uk

ABSTRACT

Cathelicidins are CHDP with essential roles in innate host defense but also more recently associated with the pathogenesis of certain chronic diseases. These peptides have microbicidal potential and the capacity to modulate innate immunity and inflammatory processes. PMN are key innate immune effector cells with pivotal roles in defense against infection. The appropriate regulation of PMN function, death, and clearance is critical to innate immunity, and dysregulation is implicated in disease pathogenesis. The efferocytosis of apoptotic PMN, in contrast to necrotic cells, is proposed to promote the resolution of inflammation. We demonstrate that the human cathelicidin LL-37 induced rapid secondary necrosis of apoptotic human PMN and identify an essential minimal region of LL-37 required for this activity. Using these LL-37-induced secondary necrotic PMN, we characterize the consequence for macrophage inflammatory responses. LL-37-induced secondary necrosis did not inhibit PMN ingestion by monocyte-derived macrophages and in contrast to expectation, was not proinflammatory. Furthermore, the anti-inflammatory effects of apoptotic PMN on activated macrophages were retained and even potentiated after LL-37-induced secondary necrosis. However, this process of secondary necrosis did induce the release of potentially harmful PMN granule contents. Thus, we suggest that LL-37 can be a potent inducer of PMN secondary necrosis during inflammation without promoting macrophage inflammation but may mediate host damage through PMN granule content release under chronic or dysregulated conditions.

Key Words: cationic host defense peptide • antimicrobial peptide • innate immunity • inflammation • efferocytosis