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 7

Rapamycin rescues LPS-induced defects in bone marrow.

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Rapamycin rescues LPS-induced defects in bone marrow. (A) Diagram of exp...
(A) Diagram of experimental design. Mice that received LPS on days 0 and 3 were treated with either vehicle (veh) or rapamycin (rapa) on days –1, 0, 2, and 3. Bone marrow cells were analyzed on day 7. (B) Rapamycin did not reduce levels of inflammatory cytokines in the plasma. Data shown are mean ± SD of plasma levels of IL-6, TNF-α, and CCL2 at 2 hours after LPS treatment (n = 5). Mice in the “Neg” group received PBS. Mice in the vehicle or rapamycin groups received LPS with either vehicle or rapamycin treatment. (C) Rapamycin prevented LPS-induced bone marrow hypocellularity. Data shown are mean ± SD of the number of bone marrow cells (n = 5). Mice in the “w/o” or LPS groups received PBS or LPS and were treated with vehicle. Mice in the rapamycin and rapamycin plus LPS groups received PBS or LPS and were treated with rapamycin. (D) Rapamycin prevented apoptosis of bone marrow cells induced by LPS. Data shown are representative FACS profiles of an experiment involving 5 mice per group. Numbers indicate the percentage of gated cells in bone marrow. (E) Inhibition of mTOR by rapamycin prevented LPS-induced loss of HSC function. 5 × 105 bone marrow cells, mixed with equal number of recipient-type bone marrow cells, were transplanted into lethally irradiated CD45.1 C57BL/6 recipients. Reconstitution ratios in the recipient peripheral blood by the donor cells were monitored at indicated time points after transplant. M, Mac-1+ myeloid cells. Data shown are mean ± SD (n = 10). *P < 0.05; **P < 0.01; ***P < 0.001.