Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice.
The mammalian target of rapamycin (mTOR) is a signaling molecule that senses environmental cues, such as nutrient status and oxygen supply, to regulate cell growth, proliferation, and other functions. Unchecked, sustained mTOR activity results in defects in HSC function. Inflammatory conditions, such as autoimmune disease, are often associated with defective hematopoiesis. Here, we investigated whether hyperactivation of mTOR in HSCs contributes to hematopoietic defects in autoimmunity and inflammation. We found that in mice deficient in Foxp3 (scurfy mice), a model of autoimmunity, the development of autoimmune disease correlated with progressive bone marrow loss and impaired regenerative capacity of HSCs in competitive bone marrow transplantation. Similarly, LPS-mediated inflammation in C57BL/6 mice led to massive bone marrow cell death and impaired HSC function. Importantly, treatment with rapamycin in both models corrected bone marrow hypocellularity and partially restored hematopoietic activity. In cultured mouse bone marrow cells, treatment with either of the inflammatory cytokines IL-6 or TNF-α was sufficient to activate mTOR, while preventing mTOR activation in vivo required simultaneous inhibition of CCL2, IL-6, and TNF-α. These data strongly suggest that mTOR activation in HSCs by inflammatory cytokines underlies defective hematopoiesis in autoimmune disease and inflammation.
Division of Immunotherapy, Department of Surgery, University of Michigan, School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Chong
C
Chen
Yu
Y
Liu
Yang
Y
Liu
Pan
P
Zheng
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
C515335:Ccr2 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases