Critical role of the mtor pathway in development and function of myeloid-derived suppressor cells in lal-/- mice

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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.

Original languageEnglish (US)
Pages (from-to)397-408
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number2
DOIs
StatePublished - Feb 1 2014

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Sirolimus
Lymphocytes
Antigens
Sterol Esterase
Bone Marrow
TOR Serine-Threonine Kinases
Cell Proliferation
Myelopoiesis
Myeloid-Derived Suppressor Cells
Cholesterol Esters
Mitochondrial Membrane Potential
Immunosuppressive Agents
Lysosomes
Nonesterified Fatty Acids
Bone Marrow Cells
Small Interfering RNA
Reactive Oxygen Species
Triglycerides
Hydrolysis
Stem Cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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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.",
author = "Xinchun Ding and Hong Du and Yoder, {Mervin C.} and Cong Yan",
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T1 - Critical role of the mtor pathway in development and function of myeloid-derived suppressor cells in lal-/- mice

AU - Ding, Xinchun

AU - Du, Hong

AU - Yoder, Mervin C.

AU - Yan, Cong

PY - 2014/2/1

Y1 - 2014/2/1

N2 - 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.

AB - 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.

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