Critical Role of the mTOR Pathway in Development and Function of Myeloid-Derived Suppressor Cells in lal−/− Mice
dc.contributor.author | Ding, Xinchun | |
dc.contributor.author | Du, Hong | |
dc.contributor.author | Yoder, Mervin C. | |
dc.contributor.author | Yan, Cong | |
dc.contributor.department | Department of Pathology and Laboratory Medicine, IU School of Medicine | en_US |
dc.date.accessioned | 2016-02-22T19:54:52Z | |
dc.date.available | 2016-02-22T19:54:52Z | |
dc.date.issued | 2014-02 | |
dc.description.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. | en_US |
dc.identifier.citation | Ding, 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.2013.10.015 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/8423 | |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier B.V. | en_US |
dc.relation.isversionof | 10.1016/j.ajpath.2013.10.015 | en_US |
dc.relation.journal | The American Journal of Pathology | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Adaptor Proteins, Signal Transducing | en_US |
dc.subject | Animals | en_US |
dc.subject | Antigens, CD11b | en_US |
dc.subject | Antigens, Ly | en_US |
dc.subject | Apoptosis | en_US |
dc.subject | Bone Marrow Cells | en_US |
dc.subject | Carrier Proteins | en_US |
dc.subject | Cell Proliferation | en_US |
dc.subject | Gene Knockdown Techniques | en_US |
dc.subject | Immunosuppression | en_US |
dc.subject | Membrane Potential, Mitochondrial | en_US |
dc.subject | Mice | en_US |
dc.subject | Myeloid Cells | en_US |
dc.subject | Phosphorylation | en_US |
dc.subject | Proto-Oncogene Proteins c-akt | en_US |
dc.subject | Reactive Oxygen Species | en_US |
dc.subject | STAT Transcription Factors | en_US |
dc.subject | Signal Transduction | en_US |
dc.subject | Sirolimus | en_US |
dc.subject | Sterol Esterase | en_US |
dc.subject | TOR Serine-Threonine Kinases | en_US |
dc.title | Critical Role of the mTOR Pathway in Development and Function of Myeloid-Derived Suppressor Cells in lal−/− Mice | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906486/ | en_US |