Abstract 550: Regulation of Macrophage Functions by a Synthetic ROR Ligand

Abstract

In the United States, approximately 16 million people suffer from coronary heart disease (CHD) and its various complications. Despite significant research effort and advances in the field of cardiovascular diseases, atherosclerosis remains the leading cause of mortality. Atherosclerosis is a multi-step inflammatory disease characterized at the early steps by accumulation of cholesterol in the arterial wall followed by recruitment of immune cells (macrophages and lymphocytes). Previous studies suggest that a member of the nuclear receptor family, retinoic-acid-receptor-related orphan receptors alpha (RORα), may play an important role in the development of atherosclerosis but mechanisms are still unclear. Recent work from our lab shows that ROR is involved in inflammatory process. We hypothesize that synthetic ROR ligands can be used as a tool to investigate the role of ROR in the regulation of inflammation and cholesterol handling and could have a therapeutic potential in the treatment of atherosclerosis. We developed a selective RORα/γ inverse agonist, SR1001, that blocks ROR activity both in vivo and in vitro. To identify the role of ROR in macrophage function, we used bone marrow derived macrophages from WT mice treated with SR1001 or DMSO control. Using an in vitro model of macrophages polarization and bio-molecular techniques, we monitor the effect of ROR in M1/M2 polarization of macrophages and NLRP3-inflammasome activity. Our results show that the ROR ligand blocks the macrophages M2 polarization and increases M1 function such as cytokines production and secretion. The ROR antagonist induces inflammation by stimulating the caspase-1-activating NLRP3 inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Decreasing M2 polarization and induction of IL-1β is associated with increased atherosclerosis. Thus, Our data suggests that ROR could play a critical role in atherosclerosis development. In conclusion, ROR could be a good target to fight inflammatory diseases such as atherosclerosis by targeting macrophages.