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

Abstract

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.

Bone mesenchymal stem cells improve cholestatic liver fibrosis by targeting ULK1 to regulate autophagy through PI3K/AKT/mTOR pathway

“… 48 Consistent with our previous study, 17 , 44 direct mTOR inhibitors, such as rapamycin, have been shown to promote autophagy and reduce apoptosis, thus stimulating HSCs activation, thereby promoting liver fibrosis. 49 , 50 Here, we identified the downstream signaling pathway PI3K/AKT/mTOR by which BMSCs regulate HSCs autophagy. As expected, our results showed that BMSCs activated PI3K/AKT/mTOR pathway to inhibit the HSCs autophagy and activation.…”

The role of transcription factors in the pathogenesis and therapeutic targeting of vascular diseases

“…IL-1β response is a crucial inflammatory pathway of foam cells involved in AS progression, which promotes the expansion of AS lesion areas along with PDGF, TNF, and M-CSF ( 95 ). Zhang et al reported that the lack of mTORC2 in macrophages significantly increased FoxO1-mediated IL-1β response and aggravated AS progression ( 11 ). Mature macrophages are important sources of foam cells.…”

“…Cell cycle regulation related TF FoxM1 promotes the proliferation of SMCs and ECs to intensify vascular remodeling ( 10 ). FoxO1 exacerbates the inflammatory response and promotes foam cell formation in response to cell stimulation, thereby exacerbating atherosclerotic lesions ( 11 ). The complete comprehension of the role of TFs in vascular diseases poses two significant challenges.…”