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Dying and Necrotic Neutrophils Are Anti-Inflammatory Secondary to the Release of -Defensins¹

Katherine Miles^*, David J. Clarke, Wuyuan Lu, Zaneta Sibinska^*, Paula E. Beaumont^*, Donald J. Davidson^*, Tom A. Barr, Dominic J. Campopiano and Mohini Gray^2,*

^* The Queen’s Medical Research Institute, School of Chemistry, College of Science and Engineering, and Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom; and Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201

Neutrophils are recruited to sites of injury but their timely removal is thought to be vital to prevent exacerbating inflammation. In addition, the recognition of apoptotic cells by cells of the innate immune system provides potent anti-inflammatory and anti-immunogenic signals. In this article, we describe how human neutrophils dying by apoptosis or necrosis release anti-inflammatory peptides, the -defensins. This family of small cationic peptides effectively inhibits the secretion of multiple proinflammatory cytokines and NO from macrophages, the main innate immune cell found at sites of chronic inflammation. In addition, the systemic administration of necrotic neutrophil supernatants and -defensins protects mice from a murine model of peritonitis. Hence. their effects may be far-reaching and serve to kill microbes while regulating a potentially tissue-destructive inflammatory response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Arthritis Research Council (to M.G. and K.H.), Engineering and Physical Sciences Research Council and Royal Society of Edinburgh (to D.J.Cl. and D.J.Ca.), and The Wellcome Trust (D.J.C.).

² Address correspondence and reprint requests to Dr. Mohini Gray, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, U.K. E-mail address: mohini.gray{at}ed.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; LDH, lactate dehydrogenase; HNP, human neutrophil peptide; HMDM, human monocyte-derived macrophage; NN, necrotic neutrophil; MOI, multiplicity of infection; NCM, neutrophil-conditioned medium; NT, necrotic murine thymocyte.