Research ArticleImmunology

Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages

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Sci. Signal.  30 Aug 2016:
Vol. 9, Issue 443, pp. ra86
DOI: 10.1126/scisignal.aaf3596

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Macrophage plasticity

Macrophages have pattern recognition receptors, such as Toll-like receptors (TLRs), through which they detect infection or tissue injury and respond by promoting inflammation or inducing wound repair. Piccinini et al. investigated how macrophages interpret the bacterial product lipopolysaccharide (LPS) and the extracellular matrix component tenascin-C, both of which stimulate TLR4. Phosphoproteomic and gene expression analyses revealed that, although both stimuli activated some common signaling pathways, LPS-stimulated macrophages were biased toward matrix destruction, whereas tenascin-C–stimulated macrophages synthesized matrix components. Together, these data reveal how activation of a single receptor by diverse stimuli generates macrophages with distinct phenotypes so that these cells can either promote inflammation or induce tissue repair.

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.

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