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Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling.

Circulation research (2023-06-23)
Xiangyu Zhang, Trent D Evans, Sunny Chen, Ismail Sergin, Jeremiah Stitham, Se-Jin Jeong, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Arick Park, In-Hyuk Jung, Abhinav Diwan, Joel D Schilling, Oren Rom, Arif Yurdagul, Slava Epelman, Jaehyung Cho, Irfan J Lodhi, Bettina Mittendorfer, Babak Razani
RÉSUMÉ

The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1β response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these 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.

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Anti--actine antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Foxo1 Inhibitor, AS1842856, Foxo1 Inhibitor, AS1842856, is a cell-permeable inhibitor that blocks the transcription activity of Foxo1 (IC₅₀ = 33 nM). Directly binds to the active Foxo1, but not the Ser256-phosphorylated form.