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Background  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 of  Rictor  inactivates mTORC2, which directly activates Akt S 473  phosphorylation and promotes pro-survival cell signaling and proliferation.    Methods and results  To study the role of mTORC2 signaling in monocytes and macrophages, we generated mice with myeloid lineage-specific  Rictor  deletion (M Rictor  −/− ). These M Rictor  −/−  mice exhibited dramatic reductions of white blood cells, B-cells, T-cells, and monocytes but had similar levels of neutrophils compared to control  Rictor  flox-flox ( Rictor  fl/fl ) mice. M Rictor  −/−  bone marrow monocytes and peritoneal macrophages expressed reduced levels of mTORC2 signaling and decreased Akt S 473  phosphorylation, and they displayed significantly less proliferation than control  Rictor  fl/fl  cells. In addition, blood monocytes and peritoneal macrophages isolated from M Rictor  −/−  mice were significantly more sensitive to pro-apoptotic stimuli. In response to LPS, M Rictor  −/−  macrophages exhibited the M1 phenotype with higher levels of pro-inflammatory gene expression and lower levels of  Il10  gene expression than control  Rictor  fl/fl  cells. Further suppression of LPS-stimulated Akt signaling with a low dose of an Akt inhibitor, increased inflammatory gene expression in macrophages, but genetic inactivation of  Raptor  reversed this rise, indicating that mTORC1 mediates this increase of inflammatory gene expression. Next, to elucidate whether mTORC2 has an impact on atherosclerosis  in vivo , female and male  Ldlr  null mice were reconstituted with bone marrow from M Rictor  −/−  or  Rictor  fl/fl  mice. 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 M Rictor  −/−  →  Ldlr  −/−  mice developed smaller atherosclerotic lesions in the distal and proximal aorta. These lesions contained less macrophage area and more apoptosis than lesions of control  Rictor  fl/fl  →  Ldlr  −/−  mice. Thus, loss of  Rictor  and, consequently, mTORC2 significantly compromised monocyte/macrophage survival, and this markedly diminished early atherosclerosis in  Ldlr  −/−  mice.    Conclusion  Our results demonstrate that mTORC2 is a key signaling regulator of macrophage survival and its depletion suppresses early atherosclerosis.

Loss of Rictor in Monocyte/Macrophages Suppresses Their Proliferation and Viability Reducing Atherosclerosis in LDLR Null Mice