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Autocrine Signalling1
* Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
Fundación Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain
Modulation of macrophage survival is a critical factor in the resolution of inflammatory responses. Exposure to LPS protects innate immune cells against apoptosis, although the precise pathways responsible for prolongation of macrophage survival remain to be fully established. The goal of this study was to characterize the mechanism of TLR4-mediated survival of murine bone marrow-derived macrophages upon M-CSF withdrawal in more detail. Using a combination of knockout mice and pharmacological inhibitors allowed us to show that TLR4 and TLR2 stimulation promotes long-term survival of macrophages in a MyD88-, PI3K-, ERK-, and NF-
B-dependent manner. LPS-induced long-term, but not short-term, survival requires autocrine signaling via TNF-
and is facilitated by a general cytoprotective program, similar to that mediated by M-CSF. TLR4-mediated macrophage survival is accompanied by a remarkable up-regulation of specific cell surface markers, suggesting that LPS stimulation leads to the differentiation of macrophages toward a mixed macrophage/dendritic cell-like phenotype.
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1 This work was supported by a Ramón y Cajal contract from the Ministerio de Educación y Ciencia of Spain (to E.L.), grants from Mutua Madrileña and Ministerio de Educación y Ciencia SAF2005-03022 (to L.B.), and National Institutes of Health Grant GM037696 (to U.G.K.).
2 Address correspondence and reprint requests to Dr. Eleuterio Lombardo, Fundación Centro Nacional de Investigaciones Cardiovasculares, Calle Melchor Fdez Almagro 3, Madrid, 28029, Spain; E-mail address: elombardo{at}cnic.es or Dr. Ulla G. Knaus, Department of Immunology IMM28, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; E-mail address: uknaus{at}scripps.edu
3 Abbreviations used in this paper: TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-
; BMDM, bone marrow-derived macrophage; cIAP, cellular inhibitor of apoptosis protein; iNOS, inducible nitric oxidase; KO, knockout; L929 CM, L929 cell-conditioned medium; LTA, lipoteichoic acid; MDDC, macrophage-derived dendritic cell; MnSOD, manganese superoxide dismutase; ox-LDL, oxidized low-density lipoprotein; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear Ag; PI, propidium iodide; SN, supernatant; WT, wild type; XIAP, X-linked inhibitor of apoptosis protein.
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