Abstract 433: Investigation Of The Divergent Roles Of Macrophage Mtor Signaling In Atherosclerosis

Abstract

The mechanistic target of rapamycin (mTOR) pathway is considered a key regulator of cellular proliferation, survival, metabolism, and degradation. Yet its role in atherosclerosis and in macrophages of the atherosclerotic plaque remains poorly understood. Our previous study has demonstrated macrophage mTORC1 signaling promotes atherogenesis through inhibiting autophagy and increasing apoptosis. Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. In contrast to the protective effect against atherosclerosis from blocking macrophage mTORC1, macrophage-specific mTORC2-deficient mice have the opposite phenotype with the development of larger and more complex lesions. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 transcription factor leading to suppression of pro-inflammatory pathways, especially the inflammasome/IL-1β response, which also manifest in vivo. In addition, administration of FoxO1 inhibitors efficiently rescued the hyperinflammation caused by mTORC2 deficiency in vitro and in vivo. Interestingly, deletion of macrophage mTOR, which ablates both mTOR-dependent pathways leads to minimal change in plaques reflecting the apparently balanced and opposing roles of its signaling arms. Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.