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Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages

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Abstract

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint. (C) 2003 Elsevier Ireland Ltd. All rights reserved

Topics: RC
Publisher: ELSEVIER SCI IRELAND LTD
OAI identifier: oai:wrap.warwick.ac.uk:9056
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