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Macrophage phagocytosis of apoptotic neutrophils is critically regulated by the opposing actions of pro-inflammatory and anti-inflammatory agents: key role for TNF-

MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK

¹Correspondence: MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ UK. E-mail: s.michlewska{at}sms.ed.ac.uk

Apoptosis of inflammatory cells and their subsequent clearance (efferocytosis) by macrophages (Ms) are key mechanisms orchestrating successful resolution of inflammation. Although the powerful proinflammatory agents lipopolysaccharide (LPS) and tumor necrosis factor (TNF-) influence rates of inflammatory cell apoptosis, little is known about their effects on efferocytosis. We have demonstrated that LPS and TNF- potently inhibit efferocytosis of neutrophils by monocyte-derived Ms. Inhibition was both concentration and time dependent, although the effect of TNF- was more rapid. We have found that soluble TNF receptor-I attenuated LPS inhibition of phagocytosis, indicating that TNF- production is critical. Inhibition of efferocytosis by LPS was found to be positively associated with M production of TNF-, but negatively with interleukin-10 (IL-10) release. A critical role for IL-10 in the regulation of phagocytosis was suggested by 2 important findings: LPS inhibition was observed more rapidly in the presence of an anti-human IL-10 receptor- antibody, and efferocytosis by IL-10-deficient Ms was markedly reduced compared to wild-type Ms. Furthermore, exogenous IL-10 and glucocorticoids reversed inhibitory effects of LPS on efferocytosis via suppression of TNF- production. We suggest that efferocytosis is regulated in an autocrine manner by pro- and anti-inflammatory mediators, and the inflammatory milieu determines whether inflammation successfully resolves.—Michlewska, S., Dransfield, I., Megson, I. L., Rossi, A. G. Macrophage phagocytosis of apoptotic neutrophils is critically regulated by the opposing actions of proinflammatory and anti-inflammatory agents: key role for TNF-.

Key Words: efferocytosis • interleukin-10 • glucocorticoids • soluble TNF-receptors