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CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer

Abstract

In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.

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Figure 1: TLR4 and TLR6 cooperatively mediate the macrophage inflammatory response to oxLDL.
Figure 2: The coreceptor CD36 is required for TLR4-TLR6-dependent responses.
Figure 3: The Alzheimer's disease peptide amyloid-β activates CD36-TLR4-TLR6 signaling.
Figure 4: CD36-TLR4-TLR6 signaling induces microglial inflammatory responses that promote neurotoxicity.
Figure 5: CD36-ligand induced TLR4-TLR6 complex formation.
Figure 6: TLR4-TLR6 activation is triggered by a membrane proximal signaling event initiated by CD36.

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Acknowledgements

We thank S. Akira (Osaka University) and K. Miyake (Japan Science and Technology Agency) for knockout mice. Supported by the US National Institutes of Health (R01AG20255 to K.J.M.; R01NS059005 to J.E.K.; R01 AG032349 to K.J.M. and J.E.K.), the Ellison Medical Foundation (K.J.M.), the American Health Assistance Foundation (A2008-130 to K.J.M.) and the Wellcome Trust (068089/Z/02/Z to L.M.S.).

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Authors and Affiliations

Authors

Contributions

C.R.S. performed the experiments using oxLDL and analyzed and interpreted the data; K.W. performed immunoprecipitation and gene expression studies; J.M.v.G. and L.B. performed confocal microscopy; J.D. and K.J.R. performed the luciferase assays; A.H. and D.T.G. generated the immortalized microglia, performed the neurotoxicity experiments and provided the TLR constructs; R.Z. and W.A.F. performed the peptide precipitation assays; J.E.K. assisted with Aβ experiments; A.L.-H. helped interpret the data and write the manuscript; L.M.S. and K.J.M. conceived the ideas, designed the research and wrote the manuscript.

Corresponding author

Correspondence to Kathryn J Moore.

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Stewart, C., Stuart, L., Wilkinson, K. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11, 155–161 (2010). https://doi.org/10.1038/ni.1836

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