The scavenger receptor CD36 has been implicated in the pathogenesis of two important chronic inflammatory diseases, atherosclerosis and Alzheimer's disease. CD36 recognition of the endogenous modified ligands, oxidized low density lipoprotein (oxLDL) and p-amyloid peptide, is believed to be central to its role in these diseases. Intriguingly, this receptor can also bind apoptotic cells and microbial ligands, and appropriately directs a non-inflammatory or pro-inflammatory host response. We postulate that: (1) CD36 binding of exogenous and modified endogenous ligands initiates signal transduction that guides the inflammatory response, and (2) the interaction of CD36 with co-receptors determines the non-inflammatory or pro-inflammatory nature of this signaling. CD36 has previously been considered to function primarily as an oxidized LDL receptor, promoting macrophage cholesterol accumulation in atherosclerosis. However, the potential of this receptor to regulate the inflammatory signaling response in this disease is untested. We recently reported that CD36 phagocytosis of S. aureus triggers Toll-like receptor signaling pathways resulting in pro-inflammatory cytokine responses. These microbial pattern recognition receptors have also been implicated in atherogenesis, raising the intriguing question of whether CD36 cooperates with Toll-like receptors to incite the pro-inflammatory signals that contribute to this disease. Our preliminary data indicate that oxidized LDL can activate CD36-Toll-like receptor signaling pathways, identifying a novel mechanism by which this pro-atherosclerotic ligand can promote inflammation. We propose that the inappropriate activation of CD36-signaling by the modified endogenous ligands oxLDL and /3-amyloid leads to inflammation resulting in disease. Our long-term goals are to understand the molecular mechanisms of CD36 pro- and non-inflammatory signaling and the impact of these pathways on disease. Identification of signaling pathways uniquely employed by specific ligands may identify targets for pharmacological interference and provide opportunities to redirect ongoing immune responses. In this proposal, we will define the molecular mechanisms that underlie the initiation of non-identical signaling cascades as a result of CD36 ligation and the implications for disease. Specifically, we will (1) define the molecular mechanisms that regulate CD36-TLR signaling, (2) define CD36 interactions that regulate pro- and non-inflammatory signaling, and (3) to examine the coexpression CD36 and TLRs in the aorta. These studies will not only improve our understanding of the mechanisms regulating CD36 signaling, but will also provide unique insights into the role of this receptor in several human disease states.
| Moore, Kathryn J; Goldberg, Ira J (2016) Emerging Roles of PCSK9: More Than a One-Trick Pony. Arterioscler Thromb Vasc Biol 36:211-2 |
| Moore, Kathryn J; Sheedy, Frederick J; Fisher, Edward A (2013) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13:709-21 |
| Sokolovska, Anna; Becker, Christine E; Ip, W K Eddie et al. (2013) Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. Nat Immunol 14:543-53 |
| Higashimori, Mie; Tatro, Jeffrey B; Moore, Kathryn J et al. (2011) Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31:50-7 |
| Moore, Kathryn J; Tabas, Ira (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341-55 |
| Fernandez-Hernando, Carlos; Moore, Kathryn J (2011) MicroRNA modulation of cholesterol homeostasis. Arterioscler Thromb Vasc Biol 31:2378-82 |
| Feig, Jonathan E; Rong, James X; Shamir, Raanan et al. (2011) HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci U S A 108:7166-71 |
| Pagler, Tamara A; Wang, Mi; Mondal, Mousumi et al. (2011) Deletion of ABCA1 and ABCG1 impairs macrophage migration because of increased Rac1 signaling. Circ Res 108:194-200 |
| Fernández-Hernando, Carlos; Suárez, Yajaira; Rayner, Katey J et al. (2011) MicroRNAs in lipid metabolism. Curr Opin Lipidol 22:86-92 |
| Wilkinson, Kim; Boyd, Justin D; Glicksman, Marcie et al. (2011) A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem 286:34914-22 |
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