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Published on: April 3, 2017
Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling
Xiangyu Zhang1,2, Trent D Evans2, Sunny Chen2
1Department of Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine and UPMC, PA (X.Z., Y.-S.Y., B.R.).
Background:
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.
Methods:
Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis.
Results:
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.
Conclusions:
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.
Insights
Targeting the mechanistic target of rapamycin (mTOR) pathway in macrophages has opposing effects on atherosclerosis. mTORC1 blockade is protective, while mTORC2 deficiency promotes plaque development by increasing inflammation.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Immunology
Background:
- The mechanistic target of rapamycin (mTOR) pathway regulates key cellular processes.
- mTOR signaling is implicated in atherosclerosis, but its specific roles in plaque macrophages are unclear.
- Previous work showed mTOR complex 1 (mTORC1) activation promotes atherosclerosis via reduced autophagy and increased macrophage apoptosis.
Purpose of the Study:
- To investigate the distinct roles of mTOR complex 2 (mTORC2) signaling in macrophage-driven atherogenesis.
- To elucidate the molecular mechanisms by which mTORC2 influences vascular inflammation and plaque progression.
Main Methods:
- Utilized macrophage-specific Rictor- and mTOR-deficient mouse models.
- Examined atherosclerotic lesion development and macrophage apoptosis in vivo.
- Investigated mTORC2 signaling effects on FoxO1 transcription factor and inflammatory pathways in cultured macrophages.
Main Results:
- Macrophage-specific mTORC2 deficiency exacerbated atherosclerosis, leading to larger, more complex plaques and increased cell death.
- mTORC2 signaling suppresses proinflammatory pathways, including the inflammasome/IL-1β response, by inhibiting FoxO1.
- FoxO1 inhibition rescued the pro-inflammatory phenotype in mTORC2-deficient macrophages both in vitro and in vivo.
- Simultaneous deletion of mTORC1 and mTORC2 in macrophages resulted in minimal changes in plaque characteristics, highlighting their opposing roles.
Conclusions:
- This study provides the first mechanistic insights into the dual roles of macrophage mTOR signaling in atherosclerosis.
- Therapeutic strategies targeting mTOR in atherosclerosis must consider the opposing functions of mTORC1 and mTORC2.
- Modulating mTORC2 signaling offers a potential avenue for controlling vascular inflammation and plaque progression.
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