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Apoptotic Cells Protect Mice against Lipopolysaccharide-Induced Shock¹

Yi Ren^2,*,,, Yi Xie^*, Guoping Jiang^*, Jianqing Fan, Joseph Yeung^*, Wen Li^*, Paul K. H. Tam^* and John Savill

^* Department of Surgery, University of Hong Kong, Hong Kong, China; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; Statistics Laboratory, Princeton University, Princeton, NJ 08854; and Medical Research Council Center for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

LPS is a main causative agent of septic shock. There is a lack of effective therapies. In vitro studies have shown that uptake of apoptotic cells actively inhibits the secretion by activated macrophages (M) of proinflammatory mediators such as TNF- and that such uptake increases the antiinflammatory and immunosuppressive cytokine TGF-β. We therefore investigated the protective effect of apoptotic cells against LPS-induced endotoxic shock in mice. The current report is the first study to demonstrate that administration of apoptotic cells can protect mice from LPS-induced death, even when apoptotic cells were administered 24 h after LPS challenge. The beneficial effects of administration of apoptotic cells included 1) reduced circulating proinflammatory cytokines, 2) suppression of polymorphonuclear neutrophil infiltration in target organs, and 3) decreased serum LPS levels. LPS can quickly bind to apoptotic cells and these LPS-coated apoptotic cells can be recognized and cleared by M in a CD14/thrombospondin/vitronectin receptor-dependent manner, accompanied with suppression of TNF- and enhancement of IL-10 expression by LPS-activated M. Apoptotic cells may therefore have therapeutic potential for the treatment of septic shock.

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 research was supported by Hong Kong Research Grants Council (HKU 7250/02M), the National Science Foundation (DMS-0714589 and DMS-0714554), and Wellcome Trust Grant 047273.

² Address correspondence and reprint requests to Dr. Yi Ren, Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, D-251, Piscataway, NJ 08854. E-mail address: ren{at}dls.rutgers.edu

³ Abbreviations used in this paper: M, macrophage; LAL, Limulus amebocyte lysate; PMN, polymorphonuclear neutrophil; TSP, thrombospondin; VnR, vitronectin receptor.