title: Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages.
abstract: Macrophages exhibit a phenotypic plasticity that enables them to orchestrate specific immune responses to distinct threats. The microbial product lipopolysaccharide (LPS) and the extracellular matrix glycoprotein tenascin-C are released during bacterial infection and tissue injury, respectively, and both activate Toll-like receptor 4 (TLR4). We found that these two TLR4 ligands stimulated distinct signaling pathways in macrophages, resulting in cells with divergent phenotypes. Although macrophages activated by LPS or tenascin-C displayed some common features, including activation of nuclear factor κB and mitogen-activated protein kinase signaling and cytokine synthesis, each ligand stimulated the production of different subsets of cytokines and generated different phosphoproteomic signatures. Moreover, tenascin-C promoted the generation of macrophages that exhibited increased synthesis and phosphorylation of extracellular matrix components, whereas LPS stimulated the production of macrophages that exhibited an enhanced capacity to degrade the matrix. These data reveal how the activation of one pattern recognition receptor by different microenvironmental cues generates macrophage with distinct phenotypes.
authors: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K.
authors: Anna M
authors: AM
authors: Piccinini
authors: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K.
authors: Lorena
authors: L
authors: Zuliani-Alvarez
authors: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K.
authors: Jenny M P
authors: JM
authors: Lim
authors: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford OX3 7FY, U.K. kim.midwood@kennedy.ox.ac.uk.
authors: Kim S
authors: KS
authors: Midwood
mesh_terms: D002478:Cells, Cultured; D060833:Cellular Microenvironment; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction; D019063:Tenascin / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C495345:TLR4 protein, human; D019063:Tenascin; D051197:Toll-Like Receptor 4