title: Requirements for apoptotic cell contact in regulation of macrophage responses.
abstract: An important consequence of macrophage engulfment of apoptotic cells is suppression of inflammatory responses, which was first defined by assay of TNF-alpha release stimulated by LPS. These effects are apparently mediated in part by paracrine effects of TGF-beta released by the subset of stimulated macrophages that ingest apoptotic cells, which suppresses neighboring cells. However, the apoptotic cell-derived signal that stimulates TGF-beta 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 alphavbeta3 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-beta in suppression by apoptotic cells, and identify an additional level of control of these effects. We show that LPS-stimulated mouse macrophage TNF-alpha release is only suppressed if macrophages have first contacted apoptotic cells, and hence, bystander macrophages are refractory to TGF-beta released by phagocytosing macrophages. We conclude that the profound suppression of LPS-driven TNF-alpha release by macrophage populations requires hitherto obscure contact-dependent licensing of macrophage responsiveness to TGF-beta by apoptotic cells.
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Lucas
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Stuart
authors.forename: Ailiang
authors.initials: A
authors.lastname: Zhang
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Roy
authors.initials: R
authors.lastname: Silverstein
authors.forename: John
authors.initials: J
authors.lastname: Savill
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology