Fibrillar Amyloid Protein Present in Atheroma Activates CD36 Signal Transduction

• Published in: The Journal of biological chemistry Vol. 279; no. 11; pp. 10643 - 10648
• Main Authors: Medeiros, Lea A., Khan, Tayeba, El Khoury, Joseph B., Pham, Chi L.L., Hatters, Danny M., Howlett, Geoffrey J., Lopez, Roland, O’Brien, Kevin D., Moore, Kathryn J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-03-2004; American Society for Biochemistry and Molecular Biology
• Subjects: Amyloid - chemistry; amyloid fibrils; Animals; apolipoprotein C-II; Arteriosclerosis - pathology; Blotting, Western; CD36 antigen; CD36 Antigens - biosynthesis; CD36 Antigens - metabolism; Cell Line, Tumor; Cells, Cultured; Foam Cells; Humans; Immunohistochemistry; Lyn protein; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Protein Binding; Protein Conformation; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; scavenger receptors; Signal Transduction; src-Family Kinases - metabolism; Time Factors; Transfection; Tumor Necrosis Factor-alpha - metabolism; Tyrosine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M311735200

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 β-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 α 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 α 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.