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 4

IL-6, TNF-α, and CCL2 are responsible for hematopoietic defects in LPS-treated mice.

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IL-6, TNF-α, and CCL2 are responsible for hematopoietic defects in LPS-t...
(A) The cytokine levels in the plasma of PBS- or LPS-treated mice at 2 or 72 hours after treatment (mean ± SD). (B) Diagram of experimental design. Six- to eight-week-old WT or Ccr2–/– mice receive LPS on days 0 and 3 (0.3 mg per mice). At both time points, the WT mice also received control mouse IgG, whereas the Ccr2–/– mice received equal amounts of mAbs specific for TNF-α and IL-6, respectively. Mice were analyzed on day 0, 3, and 7. aIL-6, anti–IL-6; aTNF-α, anti–TNF-α. (C) Involvement of inflammatory cytokines in bone marrow hypocellularity. Data shown are (mean ± SD) bone marrow cell numbers (n = 4). (D) The frequency (top) and absolute numbers (bottom) of HSCs in bone marrow after LPS treatment and cytokine blockade. WT mice were treated with control Ig, while Ccr2–/– mice received anti–IL-6 and anti-TNF-α mAbs. Mean ± SD. (E) Effect of cytokine blockade on apoptosis of HSCs at day 7. Data shown are FACS plots of DAPI and Annexin V staining and represent data from 4 mice per group. Numbers indicate the percentage of apoptotic (Annexin V+ DAPI–) and dead (Annexin V+ DAPI+) cells. (F) Role for inflammatory cytokines in LPS-induced HSC defects. WT or anti–IL-6 and anti–TNF-α–treated Ccr2–/– mice were treated with PBS or LPS twice. Four days after the second treatment, 5 × 105 bone marrow cells were mixed with equal numbers of recipient-type (CD45.1) bone marrow cells and were transplanted into lethally irradiated CD45.1 C57BL/6 recipients. Reconstitution ratios in the recipient peripheral blood by the donor cells were monitored at 4, 8, and 12 weeks after transplantation. Data shown are mean ± SD (n = 10). *P < 0.05; **P < 0.01; ***P < 0.001.