Ding, XinchunDu, HongYoder, Mervin C.Yan, Cong2016-02-222016-02-222014-02Ding, X., Du, H., Yoder, M. C., & Yan, C. (2014). Critical Role of the mTOR Pathway in Development and Function of Myeloid-Derived Suppressor Cells in lal−/− Mice. The American Journal of Pathology, 184(2), 397–408. http://doi.org/10.1016/j.ajpath.2013.10.015https://hdl.handle.net/1805/8423Lysosomal acid lipase (LAL) is essential for the hydrolysis of cholesteryl esters and triglycerides to generate cholesterol and free fatty acids in cellular lysosomes. Ablation of the lal gene (lal−/−) systemically increased expansion of cluster of differentiation molecule 11b (CD11b), lymphocyte antigen 6G (Ly6G) myeloid-derived suppressor cells (MDSCs) that caused myeloproliferative neoplasms in mice. Study of lal−/− bone marrow Ly6G+ MDSCs via transcriptional profiling showed increases in mammalian target of rapamycin (mTOR) signaling pathway transcripts. Injection of mTOR pharmacologic inhibitors into lal−/− mice significantly reduced bone marrow myelopoiesis and systemic CD11b+Ly6G+ cell expansion. Rapamycin treatment of lal−/− mice stimulated a shift from immature CD11b+Ly6G+ cells to CD11b+ single-positive cells in marrow and tissues and partially reversed the increased cell proliferation, decreased apoptosis, increased ATP synthesis, and increased cell cycling of bone marrow CD11b+Ly6G+ cells obtained from lal−/− mice. Pharmacologic and siRNA suppression of mTOR, regulatory-associated protein of mTOR, rapamycin-insensitive companion of mTOR, and Akt1 function corrected CD11b+Ly6G+ cell in lal−/− mice development from Lin− progenitor cells and reversed the immune suppression on T-cell proliferation and function in association with decreased reactive oxygen species production, and recovery from impairment of mitochondrial membrane potential compared with control mutant cells. These results indicate a crucial role of LAL-regulated mTOR signaling in the production and function of CD11b+Ly6G+ cells. The mTOR pathway may serve as a novel target to modulate the emergence of MDSCs in those pathophysiologic states in which these cells play an immunosuppressive role.en-USPublisher PolicyAdaptor Proteins, Signal TransducingAnimalsAntigens, CD11bAntigens, LyApoptosisBone Marrow CellsCarrier ProteinsCell ProliferationGene Knockdown TechniquesImmunosuppressionMembrane Potential, MitochondrialMiceMyeloid CellsPhosphorylationProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSTAT Transcription FactorsSignal TransductionSirolimusSterol EsteraseTOR Serine-Threonine KinasesArticle