title: Critical role of the mTOR pathway in development and function of myeloid-derived suppressor cells in lal-/- mice.
abstract: Lysosomal 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana; Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: hongdu@iupui.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana; Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: coyan@iupui.edu.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D007165:Immunosuppression Therapy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D002787:Sterol Esterase / Q000172:deficiency* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000950:Antigens, Ly; D039481:CD11b Antigen; D002352:Carrier Proteins; C480309:Ly6G antigen, mouse; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017382:Reactive Oxygen Species; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D050791:STAT Transcription Factors; C525637:rictor protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse; D020123:Sirolimus