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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

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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 1

Progressive bone marrow hypocellularity and HSC defects in the scurfy mice.

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Progressive bone marrow hypocellularity and HSC defects in the scurfy mi...
(A) Bone marrow cellularities of scurfy mice and their littermate controls at days 7, 14, 21, and 28 after birth. Data shown are mean ± SD (n = 4). The absolute number of bone marrow cells in scurfy and WT mice (left) and those after normalization against body weight (right) are shown. (B) HSC frequency (left) and numbers (right) in scurfy mice. Data shown are the percentage of Flk2–lin–Sca-1+c-kit+CD34–CD150+CD48– cells in bone marrow of scurfy mice and their littermate controls at days 7, 21, and 28 (mean ± SD). Each time point involves 3–5 mice per group. (C) Hyperproliferation of HSCs in day 21 scurfy (sf) mice. BrdU was labeled in vivo for 24 hours and LSK cells and HSCs were stained with BrdU antibodies. Representative histograms of BrdU staining in gated LSK cell and HSC populations and the percentage of BrdU+ population are shown. Numbers indicate the percentage of BrdU+ cells. WBM, whole bone marrow cells. Data shown are mean ± SD (n = 4). (D) Diagram of competitive bone marrow transplantation (BMT). At days 7, 21, and 28, 5 × 105 bone marrow cells from scurfy mice or those from their littermate controls were mixed with equal number of recipient-type bone marrow cells and transplanted into lethally irradiated CD45.1 C57BL/6 recipients. (E) Representative profiles of recipient peripheral blood from 28-day-old donors, evaluated at 12 weeks after reconstitution. Numbers indicate the percentage of donor-derived cells (CD45.2+, right bottom quadrants) or recipient-derived cells (CD45.1+, left top quadrants) in peripheral blood of recipient mice. (F) Reconstitution ratios in the recipient peripheral blood by the donor cells were monitored at 4 and 12 weeks after transplant. (G) Defective reconstitution in both myeloid (M) (CD11b+) and lymphoid lineages (B220+ for B cells and CD3+ for T cells). The bone marrow used are from 28-day-old mice. Data shown in F and G are mean ± SD (n = 10) from 2 independent experiments, involving 1 donor and 5 recipients per group. *P < 0.05; **P < 0.01; ***P < 0.001.

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