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* Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, United Kingdom;
Cell Adhesion and Disease Laboratory, Cancer Research U.K., London, United Kingdom; and
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
An important consequence of macrophage engulfment of apoptotic cells is suppression of inflammatory responses, which was first defined by assay of TNF-
release stimulated by LPS. These effects are apparently mediated in part by paracrine effects of TGF-
released by the subset of stimulated macrophages that ingest apoptotic cells, which suppresses neighboring cells. However, the apoptotic cell-derived signal that stimulates TGF- release, and the nature of any additional signals required for the anti-inflammatory response remain poorly defined. In this study, we investigate the requirements for apoptotic cell engagement of macrophage surface receptors in these responses. We show that the apoptotic cell receptors CD36 and v3 contribute to apoptotic cell phagocytosis by mouse macrophages, but are not essential for anti-inflammatory responses, suggesting that the mechanisms of response and phagocytosis are separate. In further defining requirements for response, we confirm the importance of TGF- in suppression by apoptotic cells, and identify an additional level of control of these effects. We show that LPS-stimulated mouse macrophage TNF- release is only suppressed if macrophages have first contacted apoptotic cells, and hence, bystander macrophages are refractory to TGF- released by phagocytosing macrophages. We conclude that the profound suppression of LPS-driven TNF- release by macrophage populations requires hitherto obscure contact-dependent licensing of macrophage responsiveness to TGF- by apoptotic cells.
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 funded by Wellcome Trust Program Grant 064487 (to J.S.). L.M.S. was funded by Wellcome Trust Clinical Training Fellowship 056647 and Wellcome Trust Clinician Scientist Fellowship 36731. A.L.-H. is funded by a United Kingdom Research Council Fellowship.
2 M.L. and L.M.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Adam Lacy-Hulbert, Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street E17-227, Cambridge, MA 02139. E-mail address: adamlh{at}mit.edu
4 Abbreviations used in this paper: PS, phosphatidylserine; TSP, thrombospondin.
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