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

Piccinini, Anna M.; Zuliani-Alvarez, Lorena; Lim, Jenny M.P.; Midwood, Kim S.

Abstract

Macrophages exhibit a phenotypic plasticity that enables them to orchestrate specific immune responses to distinct threats. However, the factors that control macrophage behaviour in a context dependent manner are not well understood. Lipopolysaccharide (LPS) and the extracellular matrix glycoprotein tenascin-C both activate toll-like receptor 4 (TLR4), and are released during bacterial infection and tissue injury, respectively. Here we report that these two TLR4 ligands induce distinct macrophage signalling pathways and phenotypes. Macrophages activated by LPS or tenascin-C display some common features, including NF-kB and MAP kinase signalling, and cytokine synthesis. However, different subsets of cytokines, and different phosphoproteomic signatures, are produced by each stimulus. Moreover, tenascin-C promotes macrophages more inclined to matrix synthesis and phosphorylation, whilst LPS-activated macrophages exhibit an elevated capacity to degrade matrix. These data reveal how activation of one pattern recognition receptor by different microenvironmental cues, signalling pathogen invasion or tissue damage, can create unique macrophage phenotypes.

Citation

Piccinini, A. M., Zuliani-Alvarez, L., Lim, J. M., & Midwood, K. S. (2016). Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages. Science Signaling, 9(443), ra86-ra86. https://doi.org/10.1126/scisignal.aaf3596

• Journal Article Type: Article
• Acceptance Date: Aug 15, 2016
• Online Publication Date: Aug 30, 2016
• Publication Date: Aug 30, 2016
• Deposit Date: Aug 22, 2016
• Publicly Available Date: Aug 30, 2016
• Journal: Science Signaling
• Print ISSN: 1945-0877
• Electronic ISSN: 1937-9145
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 443
• Article Number: ra86
• Pages: ra86-ra86
• DOI: https://doi.org/10.1126/scisignal.aaf3596
• Public URL: https://nottingham-repository.worktribe.com/output/804053
• Publisher URL: http://stke.sciencemag.org/content/9/443/ra86
• Additional Information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science signaling on 30 August 2016, Vol. 9, issue 443 DOI: 10.1126/scisignal.aaf3596