Lipopolysaccharide Reciprocally Alters the Stromal Cell-Regulated Positive and Negative Balance between Myelopoiesis and B Lymphopoiesis in C57BL/6 Mice

Abstract

Hematopoiesis in the bone marrow (BM) and spleen is controlled by stromal cells. Inflammation promotes myelopoiesis and simultaneously suppresses B lymphopoiesis. However, the role of the reciprocal regulation of myelopoiesis and B lymphopoiesis by stromal cells during inflammation is not fully understood. We investigated inflammation-induced alteration of hematopoietic regulation in lipopolysaccharide (LPS)-treated mice. C57BL/6 female mice were intravenously injected with a single, 5-µg dose of LPS, which induced a rapid decrease in the number of granulocyte-macrophage progenitors (colony-forming unit granulocyte-macrophage; CFU-GM) and B cell progenitors (CFU-preB) in BM. The CFU-GM count rapidly recovered, whereas the recovery of CFU-preB was delayed. LPS induced a marked increase in the number of CFU-GM but not in the number of CFU-preB in spleen. After LPS treatment, gene expression levels of positive regulators of myelopoiesis such as granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in BM and spleen were markedly upregulated whereas levels of positive regulators for B lymphopoiesis such as stromal cell-derived factor (SDF)-1, stem cell factor (SCF), and IL-7 remained unchanged. Meanwhile, the negative regulator of B lymphopoiesis tumor necrosis factor (TNF)-α was markedly up-regulated. The number of CFU-GM in S-phase in BM increased after LPS treatment, whereas the number of CFU-preB in S-phase decreased. These results suggest that LPS-activated stromal cells induce positive-dominant regulation of myelopoiesis and negative-dominant regulation of B lymphopoiesis, which facilitates emergency myelopoiesis during inflammation by suppressing B lymphopoiesis, thereby contributing to the host defense against infection.

Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis

“…In the same experiment, mRNA expression for various cytokines critical for maintenance of HSPCs was also evaluated ( Figure 2D). As previously reported, 21,22 LPS stimulation induced IL-6 and tumor necrosis factor (TNF)-a mRNA expression, but little or none of the other cytokine mRNAs assayed. In contrast, NOD1 stimulation under the same conditions induced IL-3, IL-7, Flt3L, SCF, and ThPO in addition to IL-6 and TNF-a mRNA expression.…”

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide

“…6) However, the down-regulation of SDF-1, IL-7, and SCF in BALB/c mice treated with 5 µg LPS was more prolonged and profound than the decreases in C57BL/6 mice treated with 5 µg LPS. These different responses to LPS between BALB/c mice and C57BL/6 mice may be due to strain-dependent differences in stromal cell sensitivity to LPS and cytokines such as TNF-α, GM-CSF, and IL-6.…”

“…6,14,15) A control group of mice was treated with the same volume of pyrogen-free saline (0.2 mL per mouse). In the early-phase experiment, three mice from each treatment group were evaluated 1, 3, and 6 h and 1, 3, 5, and 7 d after the first, second, and third treatments with LPS or saline (Fig.…”

“…Specific primers and probes for murine G-CSF, GM-CSF, IL-6, stromal cell-derived factor (SDF)-1, IL-7, stem cell factor (SCF), TNF-α, transforming growth factor (TGF)-β, and glyceraldehyde phosphate dehydrogenase (GAPDH) genes were purchased from Applied Biosystems as described elsewhere. 6,13) PCR conditions and data analysis were performed in accordance with the instructions provided with the Sequence Detection System (ver. 2.0).…”

“…3,4) This reciprocal regulation of myelopoiesis and B lymphopoiesis after LPS treatment is likely an indirect effect via stromal cells rather than a direct effect of LPS on hematopoietic cells. 5,6) Several groups recently used the mouse model of repeated low-dose LPS exposure and reported that chronic TLR signaling alters hematopoietic components. [7][8][9] Chronic (repeated) exposure of mice to LPS reduces lymphoid cells and skews the hematopoietic cell compartment toward myeloid cells, circumstances that resemble the phenotype of aged mice.…”