NR APRG
AU Medeiros,L.A.; Khan,T.; El Khoury,J.B.; Pham,C.L.; Hatters,D.M.; Howlett,G.J.; Lopez,R.; O'Brien,K.D.; Moore,K.J.
TI Fibrillar amyloid protein present in atheroma activates CD36-signal transduction
QU The Journal of Biological Chemistry 2003 Dec 29
PT journal article
AB The self-association of proteins to form amyloid fibrils has been implicated in the pathogenesis of a number of diseases, including Alzheimers, Parkinsons 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 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 TNFalpha 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 MAP kinases. Interruption of this signaling pathway, through targeted deletion of CD36 or blocking of p44/42 MAPK activation, inhibits macrophage TNFalpha 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.
AD Lipid Metabolism Unit, Massachusetts General Hospital, Boston, MA 02114.
SP englisch