Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice
Chong Chen, … , Yang Liu, Pan Zheng
Chong Chen, … , Yang Liu, Pan Zheng
Published October 25, 2010
Citation Information: J Clin Invest. 2010;120(11):4091-4101. https://doi.org/10.1172/JCI43873.
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Research Article

Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice

Abstract

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.

Authors

Chong Chen, Yu Liu, Yang Liu, Pan Zheng

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Figure 8

Hyperactivity of mTOR in HSCs causes defective hematopoiesis in the scurfy mice.

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Hyperactivity of mTOR in HSCs causes defective hematopoiesis in the scur...
(A) Hyperactivation of the mTOR pathway in HSCs. Bone marrow cells from 3-week-old scurfy mice and their littermate controls were stained with antibodies specific for phosphorylated mTOR and phosphorylated S6. Data shown are representative histograms from 2 independent experiments, each involving 2 mice per group. (B–G) Rapamycin treatment increased lifespan, reduced abnormalities in hematopoiesis, and restored HSC function in the scurfy mice. (B) Diagram of experiments. The 2-week-old scurfy mice were treated for either 1 (survival analysis) or 2 weeks (bone marrow composition and transplantation) with rapamycin (4 mg/kg/injection, every other day). (C) Short-term rapamycin treatment substantially increased lifespan of the scurfy mice. After 1 week of treatment, the mice were left untreated for observation until they were moribund. The vehicle- and rapamycin-treated groups were compared by Kaplan-Meier survival analysis, and the statistical significance was determined by log-rank test (mean ± SD; n = 8 for the vehicle group and n = 6 for the rapamycin group). (D–G) Rapamycin treatment partially restored bone marrow cellularity (D), B and myeloid cells (E), and erythroid lineage (F) development in bone marrow. Data in D–G are mean ± SD (n = 3). (G) Short-term rapamycin treatment in the scurfy mice increased their HSC function. Data shown are the percentage of CD45.2+ donor (scurfy) bone marrow–derived cells in the peripheral blood at various time points after bone marrow transplantation. Data shown are mean ± SD (n = 15) from 3 independent donors per group. *P < 0.05; **P < 0.01; ***P < 0.001.