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

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          Abstract

          In atherosclerosis and Alzheimer’s disease, deposition of the altered-self components oxidized low-density lipoprotein (LDL) and β-amyloid 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 β-amyloid trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this novel 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 β-amyloid stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by co-receptor signaling events.

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          Most cited references 42

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          Atherosclerosis--an inflammatory disease.

           R. Ross,  Paul O'Byrne (1999)
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            Toll-like receptor signalling.

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              Recognition of microorganisms and activation of the immune response.

              The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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                Author and article information

                Affiliations
                [1 ]Lipid Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
                [2 ]Laboratory of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
                [3 ]Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, 364 Plantation Street, LRB 208, Worcester, MA, 01605, USA
                [4 ]Department of Biochemistry and Molecular Biophysics, School of Medicine, Washington University, St. Louis, MO, 63110, USA
                [5 ]Centre for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA
                Author notes
                [6]

                these authors contributed equally to this work.

                [7]

                Current address: Department of Medicine, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.

                [8 ]Correspondence should be addressed to K.J.M. ( kathryn.moore@ 123456nyumc.org )

                AUTHOR CONTRIBUTIONS

                C.R.S performed the experiments using oxLDL, analyzed and interpreted the data, K.W. performed immunoprecipitation and gene expression studies, J.M.vG 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 of the ideas, designed the research and wrote the manuscript.

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                5 January 2010
                27 December 2009
                February 2010
                01 August 2010
                : 11
                : 2
                : 155-161
                20037584
                2809046
                10.1038/ni.1836
                UKMS28241

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: Wellcome Trust :
                Award ID: 068089 || WT
                Categories
                Article

                Immunology

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