Cutting Edge: LPS-Induced Emergency Myelopoiesis Depends on TLR4-Expressing Nonhematopoietic Cells

Boettcher, Steffen; Ziegler, Patrick; Schmid, Michael; Takizawa, Hajime; Rooijen, Nico van; Köpf, Manfred; Heikenwälder, Mathias; Manz, Markus G.

doi:10.4049/jimmunol.1103253

Cited by 131 publications

(149 citation statements)

References 32 publications

(22 reference statements)

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“…The enhanced engraftment potential of hematopoietic progenitors from Edil3 -/-mice was linked to a diminished potenneally injected with ultra-pure LPS twice, with an interval of 48 hours, and hematopoietic progenitors and myeloid lineage cells were analyzed at 24 hours and at 72 hours following the second injection (52,53). In this model, the initial increase in peripheral blood myeloid cells (52,53), associated with a decrease in the numbers of mature myeloid cells and CMPs in the BM, is followed by a prominent expansion of the myeloid cell compartment, as observed in Edil3 +/+ mice at 72 hours after LPS administration (Figure 8, A and B). However, the restoration of myelopoiesis in the BM was significantly attenuated in Del-1 deficiency, as shown by the decreased numbers of Gr1 hi…”

Section: Discussionmentioning

confidence: 99%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

124

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es. We show that Del-1, via its interaction with the αvβ3 integrin, promotes several critical functions in the niche, including HSC retention, hematopoietic progenitor cell cycle progression, and myeloid lineage commitment of HSCs. Del-1 thereby regulates myelopoiesis under steady-state conditions and in G-CSF-or inflammation-induced stress myelopoiesis, as well as myelopoiesis reconstitution under regenerative/transplantation conditions. Del-1 is hence a niche component that serves a juxtacrine homeostatic adaptation of the hematopoietic system in inflammation-related and regeneration myelopoiesis. ResultsDel-1 expression in the BM. First, we sought to investigate whether Del-1 is present in the BM. We initially studied the expression of the Del-1-encoding gene Edil3 in the BM niche and hematopoietic cell populations. We found that Edil3 mRNA expression was significantly higher in the endosteal region as compared with the central BM (cBM) ( Figure 1A), suggesting that Del-1 is enriched at the endosteal area of the BM. Analysis of sorted cells from CXCL12-GFP mice (33, 34) demonstrated that Edil3 was highly expressed integrin receptors (29-31). It consists of three N-terminal EGF-like repeats and two C-terminal discoidin I-like domains, and hence also is designated EGF-like repeats and discoidin-I-like domains-3 (EDIL3) (32). We have previously identified Del-1 as an endogenous modulator of leukocyte adhesion through interaction with integrin αLβ2 (LFA-1; CD11a/CD18) (29, 31). Moreover, Del-1 interacts with β3 integrin (CD61) via an Arg-Gly-Asp (RGD) motif on the second EGF-like repeat (30).In the present work, we observed that Del-1 is expressed by several major cellular components of the HSC niche, though not by hematopoietic progenitors. In particular, Del-1 is expressed by those niche cells that have a major role in the maintenance of HSCs, i.e., arteriolar endothelial cells and perivascular CAR cells (3,6,7,9,15). In addition, Del-1 is expressed by cells of the osteoblastic lineage that crucially mediate the engraftment of HSCs in the post-transplantation niche (3,17,18). This spatial distribution of Del-1 raised the possibility that it might be involved in the regulation of hematopoiesis. We addressed this hypothesis using in vivo models of steady-state, regenerative, and stress hematopoiesis and in vitro mechanistic approach-

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Section: Discussionmentioning

confidence: 99%

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Mitroulis¹,

Chen²,

Singh³

et al. 2017

Journal of Clinical Investigation

124

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“…LPS is an inflammation-inducing compound that activates stromal cells in the BM and spleen via TLR4. 18,19) Thus, LPS-treated mice are an appropriate experimental model to study how the bal- ance of positive and negative factors between B lymphopoiesis and myelopoiesis induced by stromal cells is altered during inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Increased LPS caused by Gram-negative infection initiates emergent granulopoiesis by activating stromal cells to release cytokines such as G-CSF. 18,19) Several in vitro studies showed that positive-and negative-regulator of B lymphopoiesis interact with each other. TNF-α down-regulated the expression of SDF-1 by stromal cell, 20) TGF-β also down-regulated the expressions of SDF-1, SCF and IL-7.…”

mentioning

confidence: 99%

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

Taki

Tsuboi

Harada

et al. 2014

Biological & Pharmaceutical Bulletin

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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.

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“…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.…”

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confidence: 99%

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

Tsuboi

Harada

Hirabayashi³

et al. 2016

Biological & Pharmaceutical Bulletin

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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...

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Cutting Edge: LPS-Induced Emergency Myelopoiesis Depends on TLR4-Expressing Nonhematopoietic Cells

Cited by 131 publications

References 32 publications

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche

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

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

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