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

Abstract

Chronic lipopolysaccharide (LPS) exposure to mice reduces the lymphoid compartment and skews the hematopoietic cell compartment toward myeloid-cells, which is considered to be a direct effect of LPS on hematopoietic stem cells. However, the effect of chronic LPS exposure on stromal-cells, which compose the hematopoietic microenvironment, has not been elucidated. Here, we investigated early-and late-phase effects of repeated LPS exposure on stromal-cells. During the early phase, when mice were treated with 5 or 25 µg LPS three times at weekly intervals, the numbers of myeloid-progenitor (colony forming unit-granulocyte macrophage (CFU-GM)) cells and B lymphoid-progenitor (CFU-preB) cells in the bone-marrow (BM) rapidly decreased after each treatment. The number of CFU-GM cells recovered from the initial decrease and then increased to levels higher than pretreatment levels, whereas the number of CFU-preB cells remained lower than pretreatment levels. In the BM, expression of genes for positive-regulators of myelopoiesis including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-6 and negative-regulators of B lymphopoiesis including tumor necrosis factor (TNF)-α was up-regulated, whereas expression of positive-regulators of B lymphopoiesis including stromal cell-derived factor (SDF)-1, IL-7, and stem cell factor (SCF) was down-regulated. During the late phase, the number of CFU-preB cells remained lower than pretreatment levels 70 d after the first treatments with 5 and 25 µg LPS, whereas the number of CFU-GM cells returned to pretreatment levels. IL-7 gene expression in the BM remained down-regulated, whereas gene-expression levels of SDF-1 and SCF were restored. Thus, chronic LPS exposure may impair stromal-cell function, resulting in prolonged suppression of B lymphopoiesis, which may appear to be senescence similar to the hematological phenotype.Key words hematopoiesis; stromal cell; inflammation; cytokine; local regulation Inflammation and infection alter hematopoiesis output of bone marrow (BM) by favoring myelopoiesis, especially granulopoiesis, over B lymphopoiesis.1,2) Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, induces inflammation via Toll-like receptor (TLR) 4 expressed on the cell surface. In the BM, TLR4 is expressed not only on hematopoietic cells, but also on non-hematopoietic cells such as stromal cells. Thus, LPS is a useful agent to study how hematopoiesis is regulated by stromal cells during inflammation and infection.A single injection of LPS in mice augments myelopoiesis and suppresses B lymphopoiesis, which is similar to the phenomenon observed in mice during inflammation and infection. In the BM, hematopoietic stem cells and hematopoietic progenitor cells are regulated by positive and negative factors produced by stromal cells. 3,4) This reciprocal regulation of myelopoiesis and B lymphopoiesis after LPS treatment is likely an indirect effect via stromal cells rather than a dire...

Senescence-accelerated mice (SAMP1/TA-1) treated repeatedly with lipopolysaccharide develop a condition that resembles hemophagocytic lymphohistiocytosis

“…When BALB/c mice were treated repeatedly with LPS, the numbers of white blood cells and platelets decreased rapidly after each treatment, followed by a prompt return to near or above pretreatment levels; the number of red blood cells remained unchanged. 22 Thus, the changes in the number of peripheral blood cells in SAMR1 mice after repeated LPS treatment were comparable with those in BALB/c mice after repeated LPS treatment.…”

“…Acute systemic inflammation augments myelopoiesis but suppresses B lymphopoiesis and erythropoiesis. 22,38,39 Furthermore, acute systemic inflammation provokes rapid consumption of platelets, resulting in transient thrombocytopenia. 40,41 The numbers of peripheral white blood cells, red blood cells, and platelets in SAMP1/TA-1 mice after repeated LPS treatment decreased rapidly compared with those in SAMR1 mice (Figure 1A).…”

“…Mice were injected intravenously with a single dose of 25 μg LPS three times at weekly intervals. 21,22 The body weight of non-treated SAMR1 and SAMP1/TA-1 mice was 29.6 ± 1.1 g and 31.2 ± 1.3 g, respectively. A control group of SAMR1 and SAMP1/TA-1 mice was treated with the same volume of pyrogen-free saline.…”

Clinical and Hematologic Effects of Endotoxin in Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome Model Mice

“…Thus, CXCL12/CXCR4 signaling is critical for B lymphopoiesis and accounts for severe B lymphocytopenia in WHIM syndrome, yet LPS appears to anomalously abrogate this signal in a variant WHIM receptor-specific and pre-B cellspecific manner. Inflammation is known to downregulate CXCL12 in the bone marrow, but this should have a general effect of reducing retention of cells in the bone marrow (14,24,36). In addition to directly binding to and blocking CXCR4, AMD3100 has been reported to induce downregulation of CXCL12 in the bone marrow (37,38); however, there are no studies addressing the effect of LPS on this.…”

“…CD45 lo B cells seed the spleen of LPS-challenged WHIM mice On LPS exposure, bone marrow myelopoiesis increases, whereas lymphopoiesis decreases (13,23,24). Consequently, inflammationassociated reduction of immature B cells in the bone marrow can be associated with extramedullary B lymphopoiesis in the spleen (2527).…”