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.
Highlights
CD36 is a multifunctional cell surface receptor expressed on macrophages, platelets, skeletal muscle, adipocytes, and microvascular endothelium [1]
These data indicate that apolipoprotein C-II (apoC-II) that has adopted a fibrillar amyloid conformation induces inflammatory signaling in macrophages
These data are consistent with the hypotheses that apoC-II is localized in atherosclerotic lesions in regions of macrophage accumulation and that apoC-II may form amyloid fibrils. Monocytes and their macrophage counterparts play a critical role in the innate immune response through recognition of foreign or modified host proteins/lipids. This surveillance function is mediated in part by scavenger receptors, a family of pattern recognition receptors known to bind a diverse set of ligands including modified lipoproteins, proteins modified by advanced glycation endproducts, Gram-negative bacteria, apoptotic cells, and Plasmodium parasitized erythrocytes [34]
Summary
CD36 is a multifunctional cell surface receptor expressed on macrophages, platelets, skeletal muscle, adipocytes, and microvascular endothelium [1]. CD36 is believed to participate in the innate immune response through pattern recognition of foreign or modified-host ligands As a result, this receptor has been reported to bind a diverse set of ligands including oxidized low density lipoprotein, thrombospondin-1, fatty acids, Plasmodium falciparum peptides, apoptotic cells, and most recently, -amyloid [1]. The current hypotheses suggest that lipoproteins oxidized in the artery wall stimulate an influx of monocytes, which clear these toxic lipids via scavenger receptors, including CD36 These events are believed to precipitate the accumulation of lipid-engorged macrophage foam cells, the earliest histologic evidence of atherosclerosis. ApoC-II was detected in regions that stained positive for amyloid and macrophage markers These results provide insight into the potential mechanism by which CD36 interaction with fibrillar amyloid proteins may promote inflammation in atherosclerosis
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