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Publication
Loss ofRictorin Monocyte/Macrophages Suppresses Their Proliferation and
Viability Reducing Atherosclerosis in LDLR Null Mice.
Authors Babaev VR, Huang J, Ding L, Zhang Y, May JM, Linton MF
Submitted By Submitted Externally on 3/23/2018
Status Published
Journal Frontiers in immunology
Year 2018
Date Published
Volume : Pages 9 : 215
PubMed Reference 29487597
Abstract Rictor is an essential component of mammalian target of rapamycin (mTOR) complex
2 (mTORC2), a conserved serine/threonine kinase that may play a role in cell
proliferation, survival and innate or adaptive immune responses. Genetic loss
ofRictorinactivates mTORC2, which directly activates Akt S473phosphorylation and
promotes pro-survival cell signaling and proliferation., To study the role of
mTORC2 signaling in monocytes and macrophages, we generated mice with myeloid
lineage-specificRictordeletion (MRictor-/-). These MRictor-/-mice exhibited
dramatic reductions of white blood cells, B-cells, T-cells, and monocytes but
had similar levels of neutrophils compared to controlRictorflox-flox
(Rictorfl/fl) mice. MRictor-/-bone marrow monocytes and peritoneal macrophages
expressed reduced levels of mTORC2 signaling and decreased Akt
S473phosphorylation, and they displayed significantly less proliferation than
controlRictorfl/flcells. In addition, blood monocytes and peritoneal macrophages
isolated from MRictor-/-mice were significantly more sensitive to pro-apoptotic
stimuli. In response to LPS, MRictor-/-macrophages exhibited the M1 phenotype
with higher levels of pro-inflammatory gene expression and lower levels
ofIl10gene expression than controlRictorfl/flcells. Further suppression of
LPS-stimulated Akt signaling with a low dose of an Akt inhibitor, increased
inflammatory gene expression in macrophages, but genetic inactivation
ofRaptorreversed this rise, indicating that mTORC1 mediates this increase of
inflammatory gene expression. Next, to elucidate whether mTORC2 has an impact on
atherosclerosisin vivo, female and maleLdlrnull mice were reconstituted with
bone marrow from MRictor-/-orRictorfl/flmice. After 10?weeks of the Western
diet, there were no differences between the recipients of the same gender in
body weight, blood glucose or plasma lipid levels. However, both female and male
MRictor-/-??Ldlr-/-mice developed smaller atherosclerotic lesions in the distal
and proximal aorta. These lesions contained less macrophage area and more
apoptosis than lesions of controlRictorfl/fl??Ldlr-/-mice. Thus, loss
ofRictorand, consequently, mTORC2 significantly compromised monocyte/macrophage
survival, and this markedly diminished early atherosclerosis inLdlr-/-mice., Our
results demonstrate that mTORC2 is a key signaling regulator of macrophage
survival and its depletion suppresses early atherosclerosis.




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