title: Fibrillar amyloid protein present in atheroma activates CD36 signal transduction.
abstract: The self-association of proteins to form amyloid fibrils has been implicated in the pathogenesis of a number of diseases including Alzheimer's, Parkinson's, and Creutzfeldt-Jakob diseases. We recently reported that the myeloid scavenger receptor CD36 initiates a signaling cascade upon binding to fibrillar beta-amyloid that stimulates recruitment of microglia in the brain and production of inflammatory mediators. This receptor plays a key role in the pathogenesis of atherosclerosis, prompting us to evaluate whether fibrillar proteins were present in atherosclerotic lesions that could initiate signaling via CD36. We show that apolipoprotein C-II, a component of very low and high density lipoproteins, readily forms amyloid fibrils that initiate macrophage inflammatory responses including reactive oxygen production and tumor necrosis factor alpha expression. Using macrophages derived from wild type and Cd36(-/-) mice to distinguish CD36-specific events, we show that fibrillar apolipoprotein C-II activates a signaling cascade downstream of this receptor that includes Lyn and p44/42 MAPKs. Interruption of this signaling pathway through targeted deletion of Cd36 or blocking of p44/42 MAPK activation inhibits macrophage tumor necrosis factor alpha gene expression. Finally, we demonstrate that apolipoprotein C-II in human atheroma co-localizes to regions positive for markers of amyloid and macrophage accumulation. Together, these data characterize a CD36-dependent signaling cascade initiated by fibrillar amyloid species that may promote atherogenesis.
authors.affiliation: Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Lea A
authors.initials: LA
authors.lastname: Medeiros
authors.forename: Tayeba
authors.initials: T
authors.lastname: Khan
authors.forename: Joseph B
authors.initials: JB
authors.lastname: El Khoury
authors.forename: Chi L L
authors.initials: CL
authors.lastname: Pham
authors.forename: Danny M
authors.initials: DM
authors.lastname: Hatters
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Howlett
authors.forename: Roland
authors.initials: R
authors.lastname: Lopez
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology*; D015153:Blotting, Western; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005487:Foam Cells; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000682:Amyloid; D018955:CD36 Antigens; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases