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Glucocorticoids Induce Protein S-Dependent Phagocytosis of Apoptotic Neutrophils by Human Macrophages¹

Aisleen McColl^*, Stylianos Bournazos^*, Sandra Franz^*, Mauro Perretti, B. Paul Morgan, Christopher Haslett^* and Ian Dransfield^2,*

^* Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, United Kingdom; William Harvey Research Institute Barts and London Queen Mary’s School of Medicine and Dentistry, London, United Kingdom; and Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom

During resolution of an inflammatory response, recruited neutrophil granulocytes undergo apoptosis and are removed by tissue phagocytes before induction of secondary necrosis without provoking proinflammatory cytokine production and release. Promotion of physiological neutrophil clearance mechanisms may represent a viable therapeutic strategy for the treatment of inflammatory or autoimmune diseases in which removal of apoptotic cells is impaired. The mechanism underlying enhancement of macrophage capacity for phagocytosis of apoptotic cells by the powerful anti-inflammatory drugs of the glucocorticoid family has remained elusive. In this study, we report that human monocyte-derived macrophages cultured in the presence of dexamethasone exhibit augmented capacity for phagocytosis of membrane-intact, early apoptotic cells only in the presence of a serum factor. Our results eliminate a role for a number of potential opsonins, including complement, pentraxin-3, and fibronectin. Using ion-exchange and gel filtration chromatography, we identified a high molecular mass serum fraction containing C4-binding protein and protein S responsible for the augmentation of phagocytosis of apoptotic neutrophils. Because the apoptotic neutrophils used in this study specifically bind protein S, we suggest that glucocorticoid treatment of macrophages induces a switch to a protein S-dependent apoptotic cell recognition mechanism. Consistent with this suggestion, pretreatment of macrophages with Abs to Mer tyrosine kinase, a member of the Tyro3/Axl/Mer family of receptor tyrosine kinases, prevented glucocorticoid augmentation of phagocytosis. Induction of a protein S/Mer tyrosine kinase-dependent apoptotic cell clearance pathway may contribute to the potent anti-inflammatory effects of glucocorticoids, representing a potential target for promoting resolution of inflammatory responses.

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 a European Community Grant (QLK3-CT-2002-02017), the British Heart Foundation, the Deutsche Forschungsgemeinschaft, and the Medical Research Council (United Kingdom).

² Address correspondence and reprint requests to Dr. Ian Dransfield, Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, United Kingdom. E-mail address: i.dransfield{at}ed.ac.uk

³ Abbreviations used in this paper: Dex, dexamethasone; C4BP, C4-binding protein; CMFDA, 5-chloromethylfluorescein diacetate; MDM, monocyte-derived macrophage; Mertk, Mer tyrosine kinase.