Mechanisms of cell signaling by the scavenger receptor CD36: implications in atherosclerosis and thrombosis

Abstract

CD36 is a multifunctional membrane receptor present on mononuclear phagocytes, platelets, and other cells that serves as a scavenger receptor for oxidized phospholipids, apoptotic cells and certain microbial pathogens. On macrophages, CD36 interaction with oxidized LDL (oxLDL) triggers a signaling response that is pro-inflammatory and pro-atherogenic. The signaling pathway involves activation of src-family kinases, MAP kinases, and Vav family guanine nucleotide exchange factors and results in ligand internalization, foam cell formation and inhibition of migration. On platelets, CD36 interaction with oxLDL and cell-derived microparticles transduces intracellular signals that render them more reactive to low concentrations of classical agonists. In vitro studies and in vivo experiments in CD36 null mice have revealed an important mechanistic role for CD36 in atherosclerosis and thrombosis. Identification of the precise CD36 signaling pathways in specific cells elicited in response to specific ligands may yield novel targets for drug development in athero-thrombotic disorders.

Fig. 1

Structural features of oxPC_CD36 - the signature CD36 ligands found in oxLDL. Truncated oxidized unsaturated fatty acids in the sn-2 position of glycerol-phospholipids containing a terminal aldehyde or carboxylic acid, a double bond in the beta position, and a ketone or alcohol in the gamma position are ligands for CD36. X is OH or = O; Y is H or OH.

Fig. 2

Model of microparticle MP-platelet interactions during thrombus formation. Vascular injury is induced experimentally by overlaying a piece of filter paper saturated with ferric chloride (FeCl₃) on the adventitial side of a blood vessel. This induces oxidant stress, formation of reactive oxygen species (ROS) and endothelial injury with MP release. The MP then interact with platelets in a CD36-dependent manner, enhancing platelet reactivity and becoming incorporated into the developing thrombus.

Fig. 3

Model of CD36 signaling in platelets and macrophages. CD36 binds to oxLDL or MP via a specific domain in the extracellular domain, triggering an interaction of active fyn and lyn src family kinases with its intracytoplasmic C-terminal domain. Downstream events include activation of focal adhesion kinase (FAK), upstream MAP kinase kinases (MKKK and MKK), the effector MAP kinase JNK, and the guanine nucleotide exchange factor Vav; generation of reactive oxygen species (ROS); and oxidative inactivation of the phosphatase SHP2. Together these molecular actions in macrophages lead to ligand internalization and foam cell formation as well as unregulated actin polymerization and loss of cell polarity causing a migration defect and trapping of the cells in athero-inflammatory lesions. In platelets these signaling events lead to enhanced platelet reactivity and promote thrombosis.