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.
View: Text | PDF | Corrigendum
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

×

Figure 3

LPS causes pancytopenia, bone marrow hypocellularity, and loss of HSC function.

Options: View larger image (or click on image) Download as PowerPoint
LPS causes pancytopenia, bone marrow hypocellularity, and loss of HSC fu...
(A) Diagram of experimental outline. (B) Short-term LPS treatment induces pancytopenia. Blood cell counts were measured by CBC test at indicated time points after treatment. Data shown are normalized CBC results of PBS- or LPS-treated mice at 1 week (top) or 10 weeks (bottom) after treatment. NEs, neutrophils; LYs, lymphocytes; PLTs, platelets. Mean ± SD; n = 10. (C) Bone marrow hypercellularity after LPS treatment. Data shown are (mean ± SD) numbers of bone marrow cells at 1 week after the first LPS treatment (n = 5). (D) LPS induced massive cell death in bone marrow. Data shown are representative histograms of DAPI staining. Numbers indicate the percentage of DAPI+ cells. (E–G) LPS treatment impaired the long-term reconstitution capacity of HSCs. (E) Representative profiles of donor-type (CD45.2) and recipient-type (CD45.1) blood cells 15 weeks after transplantation. Profiles depicting reconstitution of peripheral blood after transplantation with total bone marrow cells (left) and shows those reconstituted with purified HSCs (right) are shown. Numbers indicate the percentage of donor-derived cells (CD45.2+, left top quadrants) or recipient-derived cells (CD45.1+, right lower quadrants) in peripheral blood of recipient mice. (F) 5 × 105 bone marrow cells from PBS- or LPS-treated mice were mixed with equal numbers of recipient-type bone marrow cells and were transplanted into lethally irradiated CD45.1 C57BL/6 recipients. Summary data at each time point are shown (mean ± SD). (G) Fifty FACS-sorted HSCs were mixed with 100,000 recipient-type bone marrow cells. Reconstitution ratios in recipient peripheral blood by the donor cells were monitored at indicated time points after transplant. Total, all leukocytes; B, B220+ B lymphocytes; T, CD3+ T lymphocytes; M, CD11b+ myeloid cells. Data shown are mean ± SD (n = 10). *P < 0.05; **P < 0.01; ***P < 0.001.