Journal articles: 'Emergency granulopoiesis'

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Manz, Markus G., and Steffen Boettcher. "Emergency granulopoiesis." Nature Reviews Immunology 14, no. 5 (April 22, 2014): 302–14. http://dx.doi.org/10.1038/nri3660.

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Redell, Michele, S. Wen-Wen Chen, Marcos J. Ruiz, and David J. Tweardy. "Stat3β Promotes Basal Granulopoiesis and Inhibits Emergency Granulopoiesis, While Stat3α Inhibits Basal Granulopoiesis and Promotes Emergency Granulopoiesis." Blood 112, no. 11 (November 16, 2008): 3871. http://dx.doi.org/10.1182/blood.v112.11.3871.3871.

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Abstract Signal transducer and activator of transcription 3 (Stat3) is a key signaling intermediate that is activated by several cytokines that regulate hematopoiesis, including granulocyte-colony stimulating factor (G-CSF), interleukin 6, and stem cell factor (SCF). Studies using mice with Stat3 deletion targeted to hematopoietic cells have shown that Stat3 negatively regulates basal granulopoiesis but positively regulates emergency granulopoiesis. Stat3 also has been reported to promote B lymphocyte differentiation. Defining the hematopoietic functions of Stat3 is further complicated by the existence of two isoforms: full-length Stat3α (p92), and truncated Stat3β (p83). Stat3β is derived from alternative mRNA splicing resulting in replacement of the C-terminal transactivation domain with 7 unique amino acids (CT7), which have been demonstrated to confer markedly prolonged nuclear retention. Homozygous Stat3α-deficient mice are not viable, whereas Stat3β-deficient mice survive to adulthood and are fertile, but have increased inflammatory responses compared to wild-type mice. We compared basal granulopoiesis and lymphopoiesis, as well as emergency granulopoiesis, in homozygous Stat3β-deficient mice (βΔ/βΔ), which express only Stat3α, vs. their wild-type (+/+) littermates. We found that βΔ/βΔ mice were significantly leukopenic (2880 ± 1260/ml v. 4600 ± 1670/ml; p<0.05), with lower absolute neutrophil counts (ANC, 360 ± 180/ml v. 800 ± 380/ml, p<0.05) and B lymphocyte counts (780 ± 470/ml v. 1830 ± 1260/ml, p<0.05), compared to +/+ mice. Within the circulating B-lymphocyte population, the mature B220hi/IgM− cells were most dramatically reduced (170 ± 70/ml v. 480 ± 350/ml, p<0.05). Percentages of myeloid and lymphoid cells in the spleen and bone marrow were not significantly different between βΔ/βΔ and +/+ mice. Bone marrow from βΔ/βΔ mice generated significantly fewer myeloid colonies (CFU-GM) compared to wild-type marrow (28 ± 9 v. 42 ± 8 colonies per 20,000 cells, p<0.05). Additionally, βΔ/βΔ lineage-depleted bone marrow cells cultured in G-CSF and SCF produced significantly fewer CD11b+/Gr1+ myeloid cells compared to +/+ cells (52.8 ± 6.5% v. 68.3 ± 2.6%, p<0.05). In contrast, bone marrow from βΔ/βΔ and +/+ mice produced equal numbers of pro-B colonies in CFU assays containing the lymphopoietic cytokine IL-7. Finally, as a test of emergency granulopoiesis, we administered a single dose of G-CSF (250 μg/kg subcutaneously) or an equal volume of PBS, and 24 hr later measured the ANC, percentage of CD11b+/Gr1+ myeloid cells in the bone marrow, and CFU-GM generation. Mice of both genotypes responded to G-CSF stimulation with increases in ANC, percent of myeloid cells within the marrow, and CFU-GM. Bone marrow from βΔ/βΔ mice showed a larger G-CSF-induced increase in CFU-GM (PBS: 22 ± 5 v. G-CSF: 39 ± 1, p<0.05) compared to +/+ marrow (PBS: 24 ± 14 v. G-CSF: 31 ± 14, NS). Thus, Stat3β positively regulates basal granulopoiesis in the bone marrow, and may negatively regulate emergency granulopoiesis. This pattern is the opposite of that seen with deletion of both Stat3 isoforms, indicating that Stat3α’s function is to negatively regulate basal granulopoiesis and positively regulate emergency granulopoiesis. Stat3β also positively regulates circulating B lymphocyte numbers, via a mechanism other than B lymphocyte production in the bone marrow.

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Wirths, Stefan, Stefanie Bugl, Markus P. Radsak, Melanie Märklin, Martin R. Müller, Lothar Kanz, and Hans-Georg Kopp. "Bone Marrow Derived Mesenchymal Cells Secrete Granulopoietic Cytokines upon Danger Signaling." Blood 124, no. 21 (December 6, 2014): 4115. http://dx.doi.org/10.1182/blood.v124.21.4115.4115.

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Abstract Granulopoietic homeostasis is regulated at steady-state to supply sufficient numbers of pooled and circulating neutrophils to maintain barrier function against commensal flora. In addition, upon pathogenic microbial challenge, an increased formation of neutrophils is induced, termed ‘emergency granulopoiesis’. Antibody-mediated reduction of neutrophil numbers in steady-state induces a feedback loop leading to an increase of bone marrow granulopoiesis with expansion of hematopoetic stem and progenitor cells. This feedback loop was demonstrated to depend on TLR4 and TRIF, but not MyD88 signaling (Bugl et al. Blood 2013). In contrast, emergency granulopoiesis was shown to be dependent on MyD88 signaling in endothelial cells (Boettcher et al. Blood 2014). Bone marrow mesenchymal stromal cells (MSC) are niche-forming cells, harboring and regulating hematopoiesis. Upon steady-state neutropenia an increase of niche size was observed. Here we investigated, whether niche-forming MSC act as sensors of pathogen-associated molecular patterns (PAMPs) and induce granulopoietic cytokines to stimulate expansion of adjacent hematopoietic stem and progenitor cells. MSC of C57BL/6 and TLR4-KO mice were cultured in vitro and treated with LPS for 24 hours. Cells were harvested and qRT-PCR for G-CSF, TLR4, MyD88, TRIF, GM-CSF, IL-1β, IL-18 and Casp-1 was performed After treatment with LPS, RNA of granulopoietic cytokines G-CSF and GM-CSF were massively up regulated in MSC of WT mice. Upstream regulating, inflammasome components IL-1ß and caspase-1 RNA levels increased as well, with little changes in IL-18, TLR4, MyD88 and TRIF. Unexpectedly, TLR4-KO MSC up regulated transcription of IL-1β and G-CSF upon LPS stimulation as well, and caspase-1 was found to be strongly up-regulated in unstimulated TLR4-KO compared to WT MSC. In summary, bone marrow stromal cells are found to be PAMP-sensing and secrete cytokines that regulate granulopoiesis. TLR4-independent sensing of LPS by MSC might correspond to the alternative noncanonical inflammasome pathway recently described (Kayagaki et al. Science 2013). Disclosures No relevant conflicts of interest to declare.

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Hu, Liping, Weiqi Huang, Ling Bei, Larisa Broglie, and Elizabeth A. Eklund. "TP53Haploinsufficiency Rescues Emergency Granulopoiesis inFANCC−/−Mice." Journal of Immunology 200, no. 6 (February 2, 2018): 2129–39. http://dx.doi.org/10.4049/jimmunol.1700931.

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Zhang, Huiyuan, Hoainam Nguyen-Jackson, Athanasia D. Panopoulos, Haiyan S. Li, Peter J. Murray, and Stephanie S. Watowich. "STAT3 controls myeloid progenitor growth during emergency granulopoiesis." Blood 116, no. 14 (October 7, 2010): 2462–71. http://dx.doi.org/10.1182/blood-2009-12-259630.

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Abstract Granulocyte colony-stimulating factor (G-CSF) mediates “emergency” granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF–dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF–responsive myeloid progenitor expansion.

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Wang, Hao, Chirag A. Shah, Liping Hu, Weiqi Huang, Leonidas C. Platanias, and Elizabeth A. Eklund. "An aberrantly sustained emergency granulopoiesis response accelerates postchemotherapy relapse in MLL1-rearranged acute myeloid leukemia in mice." Journal of Biological Chemistry 295, no. 28 (May 28, 2020): 9663–75. http://dx.doi.org/10.1074/jbc.ra120.013206.

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Acute myeloid leukemia (AML) with mixed lineage leukemia 1 (MLL1) gene rearrangement is characterized by increased expression of a set of homeodomain transcription factors, including homeobox A9 (HOXA9) and HOXA10. The target genes for these regulators include fibroblast growth factor 2 (FGF2) and Ariadne RBR E3 ubiquitin ligase 2 (ARIH2). FGF2 induces leukemia stem cell expansion in MLL1-rearranged AML. ARIH2 encodes TRIAD1, an E3 ubiquitin ligase required for termination of emergency granulopoiesis and leukemia suppressor function in MLL1-rearranged AML. Receptor tyrosine kinases (RTKs), including the FGF receptor, are TRIAD1 substrates that are possibly relevant to these activities. Using transcriptome analysis, we found increased activity of innate immune response pathways and RTK signaling in bone marrow progenitors from mice with MLL1-rearranged AML. We hypothesized that sustained RTK signaling, because of decreased TRIAD1 activity, impairs termination of emergency granulopoiesis during the innate immune response and contributes to leukemogenesis in this AML subtype. Consistent with this, we found aberrantly sustained emergency granulopoiesis in a murine model of MLL1-rearranged AML, associated with accelerated leukemogenesis. Treating these mice with an inhibitor of TRIAD1-substrate RTKs terminated emergency granulopoiesis, delayed leukemogenesis during emergency granulopoiesis, and normalized innate immune responses when combined with chemotherapy. Emergency granulopoiesis also hastened postchemotherapy relapse in mice with MLL1-rearranged AML, but remission was sustained by ongoing RTK inhibition. Our findings suggest that the physiological stress of infectious challenges may drive AML progression in molecularly defined subsets and identify RTK inhibition as a potential therapeutic approach to counteract this process.

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Tamura, Akihiro, Hideyo Hirai, Yoshihiro Hayashi, Hisayuki Yao, Satoshi Yoshioka, Yasuo Miura, Eishi Ashihara, and Taira Maekawa. "C/EBPβ-Mediated Expansion of Hematopoietic Stem/Progenitors Precedes ‘Emergency’ Granulopoiesis Induced by Candidemia." Blood 120, no. 21 (November 16, 2012): 2336. http://dx.doi.org/10.1182/blood.v120.21.2336.2336.

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Abstract Abstract 2336 Granulopoiesis, the process of granulocyte production in the bone marrow (BM), is tightly regulated to meet host demands during both 'steady state' and 'emergency' situations such as infections. The transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) plays critical roles in emergency granulopoiesis (Hirai et al. Nat Immunology, 2006). However, the precise developmental stages in which C/EBPβ is required are unknown. In this study, we investigated the roles of C/EBPβ in the proliferation and differentiation of prospectively identified intermediates between hematopoietic stem cells and mature granulocytes in mouse BM. In order to analyze the mouse BM cells undergoing granulopoiesis, novel flow cytometric method was developed. Mouse BM cells retaining the ability to give rise to granulocytes were dissected into five distinct subpopulations (#1–#5) according to their levels of c-kit and Ly-6G expression. Upon infection of Candida albicans (4 × 106 CFU/20 g body weight/mouse) on day 1, C/EBPβ was upregulated at the protein level but not at mRNA level in all the granulopoietic subpopulations, suggesting the importance of the transcription factor in □emergency' granulopoiesis. Then, the role of C/EBPβ was further assessed by analyzing C/EBPβ knockout (KO) mice. At steady state, the distribution of granulopoietic cells in BM of C/EBPβ KO mice at □esteady state' was identical to that of wild type (WT) mice. In contrast, the rapid increase in immature subpopulations #1 and #2 observed in WT mice at 1 day post-infection was significantly attenuated in C/EBPβ KO mice. The levels of mRNA expression for granule proteins (cathepsin G, myeloperoxidase, elastase 2, proteinase 3, lactoferrin and MMP9) within each subpopulation from WT and C/EBPβ KO mice were identical at both steady state and during infection. When the cell cycle status of these models was evaluated using in vivo BrdU labeling experiments, incorporation of BrdU in subpopulation #1 and #2 in C/EBPβ KO mice was always slightly lower than in WT mice, but the differences were not statistically significant. These findings suggest that C/EBPβ is required for efficient proliferation of early granulocytic precursors but not directly involved in the differentiation/maturation process. To elucidate the roles of C/EBPβ in the proliferation of the early granulopoietic subpopulations, the hematopoietic stem cells (HSCs) and myeloid progenitor compartments were analyzed in WT and C/EBPβ KO mice. The frequency and number of c-kit+ Sca-1+ lineage markers− HSC were identical between WT mice and C/EBPβ KO mice during the steady state, and were not significantly affected on day 1 post-infection. Induction of candidemia increased the frequency and number of granulocyte-macrophage progenitors (GMP) in WT mice, and these increases were significantly attenuated in C/EBPβ KO mice. Upon induction of candidemia, the frequency of BrdU-positive cells in the HSC and common myeloid progenitors (CMP) populations from WT mice increased significantly; however, an increase of BrdU-positive cells was observed only within the HSC compartment in C/EBPβ KO mice, and at a lower level than that in WT mice Taken together, these data suggest that the proliferation of early granulocytic precursors is tightly coupled to differentiation/maturation and that C/EBPβ is involved in the efficient amplification of early granulocyte precursors including HSC and myeloid progenitors during candidemia-induced 'emergency' granulopoiesis. Disclosures: No relevant conflicts of interest to declare.

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Satake, Sakiko, Hideyo Hirai, Nobuaki Shime, Rina Nagao, Ruriko Tanaka, Hisayuki Yao, Yoshihiro Hayashi, et al. "Candidemia-Induced Emergency Granulopoiesis Consists of Successive Dual Waves Triggered by the Shift From C/EBPalpha to C/EBPbeta Dependency." Blood 116, no. 21 (November 19, 2010): 3778. http://dx.doi.org/10.1182/blood.v116.21.3778.3778.

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Abstract Abstract 3778 Introduction: Granulocyte is a major cellular component in the front line of host defense. The number of granulocytes must be tightly tuned to meet the demand, because both the shortage and the excess of granulocytes can be harmful to the host. During emergency situations such as infections, granulocytes are replenished from peripheral pools and bone marrow production. As the half-life of granulocytes is quite short, granulopoiesis, de novo production of granulocytes in bone marrow, plays an important role during emergency. We have previously shown that granulopoiesis at steady state is largely dependent on a transcription factor, C/EBPalpha, whereas emergency granulopoiesis is dependent on C/EBPbeta (Hirai H, et al. Nature Immunol., 2006). However, the precise developmental stage where the shift from C/EBPalpha dependency to C/EBPbeta dependency takes place is almost unknown. The aim of this study is to dissect the process of granulopoiesis by a novel flow cytometric method and to elucidate the molecular mechanisms involved in the regulation of emergency granulopoiesis. Methods: 4 ≂ 106 cfu Candida albicans were intravenously injected to induce emergency granulopoiesis. Mouse bone marrow cells were harvested and stained with a combination of fluorescent-conjugated antibodies including anti-c-kit, anti-CD34, anti-Ly6G antibodies and markers for other lineages. Then the stained cells were analyzed or sorted by flow cytometry. After eliminating the cells which lost potential to give rise to granulocytes, the remaining cells were dissected into five subpopulations (#1≂ #5) according to the expression levels of c-kit and Ly6G. #1 is c-kithigh Ly6Glow cells, @ #2: c-kitint Ly6Glow, #5: c-kitlow Ly6Ghigh, and the cells residing between #2 and #5 are divided into #3 and #4. Cell number, gene expressions and cell cycle status of each population were analyzed before and after inducing emergency granulopoiesis. @ Results and Discussions: Wright-Giemsa staining and qRT-PCR for granule proteins (cathepsin G, myeloperoxidase, neutrophil elastase2, lactoferrin and MMP9) in each population indicated that lower c-kit expression and higher Ly6G expression correlated well with granulocytic differentiation and that the granulopoiesis progresses from # 1 to #5 in this order both at steady state and during emergencies (Figure 1). Then we applied this method to candidemia-induced emergency granulopoiesis. In vivo BrdU incorporation analysis showed immediate acceleration of the cell cycle in the most immature population (#1) and in one of the intermediate populations (#2). Chronological monitoring of each population after inducing candidemia revealed that rapid increase in mature granulocytes (#5) preceded the replenishment from the most immature population (#1). These results suggested that there are two distinct gwavesh in granulopoiesis at the early phase of infection, a rapid supply (first gwaveh) of granulocytes from relatively mature population (#2≂ #4), and a further and sustained supply (second gwaveh) originated from more immature populations (#1) including hematopoietic stem/progenitor cells (Figure 1). Transcripts of C/EBPalpha were significantly downregulated in #1≂ #4 at the early phase of infection, while those of C/EBPbeta were maintained in all the subpopulation (Figure 2), suggesting that shift from C/EBPalpha dependency to C/EBPbeta dependency took place at multiple developmental steps in granulopoiesis. C/EBPbeta has less inhibitory effects on cell cycle than C/EBPalpha while their abilities to induce granulocytic differentiation are similar (Hirai H, et al. Nature Immunol., 2006). The shift toward C/EBPbeta dependency may trigger the dual waves in emergency granulopoiesis, which demands both differentiation and proliferation of granulocytic precursors. Disclosures: No relevant conflicts of interest to declare.

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Hirai, Hideyo, Pu Zhang, Tajhal Dayaram, Christopher J. Hetherington, Shin-ichi Mizuno, Jiro Imanishi, Koichi Akashi, and Daniel G. Tenen. "C/EBPβ is required for 'emergency' granulopoiesis." Nature Immunology 7, no. 7 (June 4, 2006): 732–39. http://dx.doi.org/10.1038/ni1354.

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Zhang, Huiyuan, Hoainam Nguyen-Jackson, Athanasia Panopoulos, Haiyan S. Li, Peter J. Murray, and Stephanie Watowich. "STAT3 Controls Neutrophil Progenitor Growth and Differentiation During Emergency Granulopoiesis." Blood 114, no. 22 (November 20, 2009): 3619. http://dx.doi.org/10.1182/blood.v114.22.3619.3619.

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Abstract Abstract 3619 Poster Board III-555 Granulocyte colony-stimulating factor (G-CSF) controls neutrophil production in the bone marrow under steady state conditions and during demand-driven hematopoiesis occurring in response to infection. STAT3 is a principal signaling molecule activated by the G-CSF receptor (G-CSFR). We previously reported that STAT3 has an important role in demand-driven granulopoiesis, although its cellular and molecular mechanisms have been unclear. To address this, we investigated STAT3 function in emergency granulopoiesis stimulated by G-CSF administration or infection with Listeria monocytogenes, which is restrained by the G-CSF response pathway in vivo. Our results show that STAT3-deficiency renders hematopoietic stem cells and myeloid progenitors refractory to the proliferation-inducing effects of G-CSF or Listeria monocytogenes infection. STAT3-deficient myeloid progenitors have a cell autonomous defect in G-CSF-responsive cell cycle progression and undergo delayed granulocyte maturation relative to wild type cells. To define STAT3 target pathways in granulocytic progenitors, we investigated the expression of CCAAT enhancer binding protein (C/EBP) beta, a transcription factor that is necessary for G-CSF-driven emergency granulopoiesis. We found that STAT3 directly regulates G-CSF-responsive C/EBPbeta expression by binding to Cebpb promoter. Moreover, we show that STAT3 and C/EBPbeta co-regulate c-Myc during emergency granulopoiesis. These results place STAT3 as a crucial G-CSF-responsive signal transducer during demand-driven granulopoiesis, through its regulation of critical transcription factors in developing granulocytes. Disclosures: Zhang: Amgen: Research Funding. Nguyen-Jackson:Amgen: Research Funding. Watowich:Amgen, Inc: Research Funding.

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Lieschke, GJ, D. Grail, G. Hodgson, D. Metcalf, E. Stanley, C. Cheers, KJ Fowler, S. Basu, YF Zhan, and AR Dunn. "Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization." Blood 84, no. 6 (September 15, 1994): 1737–46. http://dx.doi.org/10.1182/blood.v84.6.1737.1737.

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Abstract Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G- CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G- CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF- /- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during “steady-state” granulopoiesis in vivo and also implicate G-CSF in “emergency” granulopoiesis during infections.

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Lieschke, GJ, D. Grail, G. Hodgson, D. Metcalf, E. Stanley, C. Cheers, KJ Fowler, S. Basu, YF Zhan, and AR Dunn. "Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization." Blood 84, no. 6 (September 15, 1994): 1737–46. http://dx.doi.org/10.1182/blood.v84.6.1737.bloodjournal8461737.

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Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G- CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G- CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF- /- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during “steady-state” granulopoiesis in vivo and also implicate G-CSF in “emergency” granulopoiesis during infections.

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Zhang, Ping, Lee J. Quinton, Lisa Gamble, Gregory J. Bagby, Warren R. Summer, and Steve Nelson. "THE GRANULOPOIETIC CYTOKINE RESPONSE AND ENHANCEMENT OF GRANULOPOIESIS IN MICE DURING ENDOTOXEMIA." Shock 23, no. 4 (April 2005): 344–52. http://dx.doi.org/10.1097/01.shk.0000158960.93832.de.

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Bugl, Stefanie, Stefan Wirths, Markus P. Radsak, Hansjörg Schild, Pamela Stein, Maya C. André, Martin R. Müller, et al. "Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling." Blood 121, no. 5 (January 31, 2013): 723–33. http://dx.doi.org/10.1182/blood-2012-05-429589.

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Kreisel, Daniel, Seiichiro Sugimoto, Jihong Zhu, Ruben Nava, Wenjun Li, Mikio Okazaki, Sumiharu Yamamoto, et al. "Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance." Blood 118, no. 23 (December 1, 2011): 6172–82. http://dx.doi.org/10.1182/blood-2011-04-347823.

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Abstract The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c+ dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ+ T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF–mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF–mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

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Wang, Hao, Ling Bei, Chirag A. Shah, Liping Hu, and Elizabeth A. Eklund. "HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1." Journal of Immunology 194, no. 11 (April 20, 2015): 5375–87. http://dx.doi.org/10.4049/jimmunol.1401909.

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Pedersen, Corinna Cavan, Rehannah Borup, Anne Fischer-Nielsen, Helena Mora-Jensen, Anna Fossum, Jack B. Cowland, and Niels Borregaard. "Changes in Gene Expression during G-CSF-Induced Emergency Granulopoiesis in Humans." Blood 126, no. 23 (December 3, 2015): 2202. http://dx.doi.org/10.1182/blood.v126.23.2202.2202.

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Abstract Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for granulocyte colony-stimulating factor (G-CSF) as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been elucidated in humans. Here, we investigate the changes in mRNA and miRNA expression in successive stages of neutrophil development following in vivo administration of G-CSF in humans, mimicking emergency granulopoiesis. Blood samples were collected from healthy individuals after five days of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry and extracted RNA was subjected to microarray analysis. mRNA levels were compared to previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. miRNA expression was investigated in the most mature cell population to determine G-CSF-induced changes in circulating neutrophils. G-CSF substantially affected mRNA and miRNA expression patterns, demonstrating significant impact on neutrophil development and function. 1110 mRNAs were differentially expressed more than 2-fold with G-CSF while the treatment induced changes in the levels of 73 miRNAs in the mature population. In addition, G-CSF treatment reduced the levels of four out of five measured granule proteins in mature neutrophils including hCAP-18, which was completely deficient in neutrophils from G-CSF-treated donors. Cell cycle analysis pointed towards an induced proliferative capacity of myelocytes. These results indicate that multiple biological processes are altered in order to satisfy the increased demand for neutrophils during G-CSF-induced emergency granulopoiesis. Disclosures No relevant conflicts of interest to declare.

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Boettcher, Steffen, Rahel C. Gerosa, Ramin Radpour, Judith Bauer, Franziska Ampenberger, Mathias Heikenwalder, Manfred Kopf, and Markus G. Manz. "Endothelial cells translate pathogen signals into G-CSF–driven emergency granulopoiesis." Blood 124, no. 9 (August 28, 2014): 1393–403. http://dx.doi.org/10.1182/blood-2014-04-570762.

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Key Points ECs express Tlr4 and Myd88 and, after in vivo LPS or E coli stimulation, are the prime sources of G-CSF. ECs are sensors of systemically spread pathogens and subsequent drivers of BM emergency granulopoiesis.

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Kardosova, Miroslava, Polina Zjablovskaja, Petr Danek, Pavla Angelisova, Lorena Lobo de Figueiredo-Pontes, Robert S. Welner, Tomas Brdicka, Sanghoon Lee, Daniel G. Tenen, and Meritxell Alberich-Jorda. "C/EBPγ is dispensable for steady-state and emergency granulopoiesis." Haematologica 103, no. 8 (March 22, 2018): e331-e335. http://dx.doi.org/10.3324/haematol.2017.173781.

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Panopoulos, A. D., L. Zhang, J. W. Snow, D. M. Jones, A. M. Smith, K. C. El Kasmi, F. Liu, et al. "STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils." Blood 108, no. 12 (December 1, 2006): 3682–90. http://dx.doi.org/10.1182/blood-2006-02-003012.

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Parsa, Roham, Harald Lund, Anna-Maria Georgoudaki, Xing-Mei Zhang, André Ortlieb Guerreiro-Cacais, David Grommisch, Andreas Warnecke, et al. "BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis." Journal of Experimental Medicine 213, no. 8 (July 18, 2016): 1537–53. http://dx.doi.org/10.1084/jem.20150577.

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Prolonged infections or adjuvant usage can trigger emergency granulopoiesis (EG), leading to dysregulation in neutrophil blood counts. However, the impact of EG on T and B cell function remains largely unknown. In this study, to address this question, we used a mouse model of neutropenia and studied immune activation after adjuvant administration. The initial neutropenic state fostered an environment of increased dendritic cell activation and T cell–derived IL-17 production. Interestingly, neutropenic lysozyme 2–diphtheria toxin A mice exhibited striking EG and amplified neutrophil recruitment to the lymph nodes (LNs) that was dependent on IL-17–induced prostaglandin activity. The recruited neutrophils secreted a B cell–activating factor that highly accelerated plasma cell generation and antigen-specific antibody production. Reduction of neutrophil functions via granulocyte colony-stimulating factor neutralization significantly diminished plasma cell formation, directly linking EG with the humoral immune response. We conclude that neutrophils are capable of directly regulating T cell–dependent B cell responses in the LN.

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Cain, Derek W., Pilar B. Snowden, Gregory D. Sempowski, and Garnett Kelsoe. "Inflammation Triggers Emergency Granulopoiesis through a Density-Dependent Feedback Mechanism." PLoS ONE 6, no. 5 (May 31, 2011): e19957. http://dx.doi.org/10.1371/journal.pone.0019957.

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Hu, Liping, Weiqi Huang, Elizabeth Hjort, and Elizabeth A. Eklund. "Increased Fanconi C expression contributes to the emergency granulopoiesis response." Journal of Clinical Investigation 123, no. 9 (August 8, 2013): 3952–66. http://dx.doi.org/10.1172/jci69032.

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Hirai, Hideyo, Naoka Kamio, Akiko Matsusue, Shinpei Ogino, Nobuhiko Kimura, Sakiko Satake, Eishi Ashihara, Taira Maekawa, Daniel G. Tenen, and Jiro Imanishi. "CREB Is Involved in the Regulation of C/EBPβ During 'emergency' Granulopoiesis." Blood 114, no. 22 (November 20, 2009): 1457. http://dx.doi.org/10.1182/blood.v114.22.1457.1457.

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Abstract Abstract 1457 Poster Board I-480 Mobilization of sufficient numbers of granulocytes to the front line of infection is prerequisite for host defense. As granulocytes have a short half-life, the production of granulocytes in the bone marrow must be tightly regulated to meet emergency demands. Our previous findings suggested that granulopoiesis at steady state is largely dependent on CCAAT enhancer binding protein α (C/EBPα) transcription factor (Zhang D.E. et al., PNAS, 1996 and Zhang P. et al., Immunity, 2004), whereas the granulopoiesis during emergency such as infections is dependent upon C/EBPβ (Hirai H. et al., Nat Immunology, 2006). Indeed the transcripts of C/EBPβ in granulocyte precursors were upregulated in response to cytokine stimulation or infection. In order to elucidate the molecular switch between C/EBPα- and C/EBPβ-dependent granulopoiesis, we developed a novel lentivirus-based reporter system. The vector carries two independent expression units, a green fluorescent protein (GFP) driven by a promoter of interest and a mouse Thy1.1 gene under the control of a constitutively active phosphoglycerate kinase (PGK) promoter. The activity of a promoter can be monitored by the intensity of GFP in Thy1.1 positive cells. Using this system, the activity of the C/EBPβpromoter was evaluated in primary bone marrow cells. A series of deletion mutants of the promoter revealed the existence of two cyclic AMP responsive elements (CRE) in the positive responsive elements during GM-CSF induced differentiation. The transcripts of CRE binding (CREB) protein were detected at higher level in hematopoietic stem cells and common myeloid progenitors than other mature cells. When a dominant negative mutant of CREB (S133A), in which the serine residue at 133aa was mutated to alanine, was retrovirally transduced into bone marrow cells, the mRNA of C/EBPβ was reduced and the proliferation/differentiation of granulocyte precursors were significantly impaired. In contrast, a constitutively active form of CREB, CREBDIEDML, facilitated the transcription of C/EBPβ. In addition, CREB is phosphorylated and bound to the CRE in response to GM-CSF stimulation. These data suggest that CREB is involved in the regulation of granulopoiesis through upregulation of C/EBPβ. Disclosures No relevant conflicts of interest to declare.

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Moreau, Joshua M., Alexandra Berger, Megan E. Nelles, Michael Mielnik, Caren Furlonger, Selena Y. Cen, Rickvinder Besla, Clinton S. Robbins, and Christopher J. Paige. "Inflammation rapidly reorganizes mouse bone marrow B cells and their environment in conjunction with early IgM responses." Blood 126, no. 10 (September 3, 2015): 1184–92. http://dx.doi.org/10.1182/blood-2015-03-635805.

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Key Points Mouse inflammation models cause accumulation of B cells in the bone marrow within 12 hours and prior to peak emergency granulopoiesis. Marrow B cells undergo spatial reorganization and are subjected to an altered cellular and secreted milieu.

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Dan, Lan, Basant Kumar Thakur, Julia Skokowa, and Karl Welte. "The in Vivo Response of Patients Suffering from Severe Congenital Neutropenia (CN) to G-CSF Is Due to “Emergency” Granulopoiesis Induced by C/EBPβ." Blood 112, no. 11 (November 16, 2008): 315. http://dx.doi.org/10.1182/blood.v112.11.315.315.

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Abstract C/EBP transcription factors are crucial for the regulation of granulopoiesis in vitro and in vivo. C/EBPa is considered to be the master regulator of “steady state” granulopoiesis via upregulation of several myeloid genes (e.g. ELA2, CSFR3, etc.). The absence of C/ EBPa results in a complete loss of neutrophils. We were able to show that in patients with severe congenital neutropenia (CN) harbouring HAX-1 or ELA2 mutations C/EBPa is severely abrogated secondary to defective expression of LEF-1 (Skokowa J, et al. Nat Med.12, 1191–7 (2006)). Therefore, we were interested, whether other transcription factors are capable of substituting C/EBPa, since these patients respond to G-CSF with slight increase in neutrophils from less than 200/ul to above 1500/ul depending on the dose of G-CSF. C/EBPβ has recently been shown to be required for cytokine induced “emergency” granulopoiesis (Hirai H, et al. Nat Immunol.7, 732-9 (2006)). Therefore, we investigated the expression pattern of C/EBPβ during G-CSF treatment of CN patients. Indeed, C/EBPβ mRNA was upregulated 2.8-fold in CD33+ myeloid cells from CN patients by G-CSF treatment, as compared to healthy individuals. It was associated with upregulation of G-CSFR mRNA and –protein expression as well as ligand binding to G-CSFR in myeloid cells, and elevated levels of biologically active G-CSF in serum from CN patients. To confirm C/EBPβ-dependent activation of G-CSFR and G-CSF gene expression, we performed reporter gene assays in CD34+ bone marrow hematopoietic progenitor cells from two CN patients co-transfected with C/EBPβ and reporter constructs containing upstream regulatory regions of G-CSF or G-CSFR genes, −1470bp and −670bp, respectively. Indeed, C/EBPβ activated G-CSFR promoter 3.2-fold and G-CSF promoter 5.4-fold. These data demonstrate that in CN patients, G-CSF induces C/EBPa independent granulopoiesis and that C/EBPβ is required for the response to G-CSF treatment in these patients. C/EBPβ leads in response to G-CSF to induction of differentiation of neutrophil precursors to mature neutrophils in vivo. Our hypothesis is that in CN the steady state granulopoiesis is abrogated whereas the emergency granulopoiesis still leads to sufficient numbers of neutrophils.

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Brook, Byron, Danny J. Harbeson, Casey P. Shannon, Bing Cai, Daniel He, Rym Ben-Othman, Freddy Francis, et al. "BCG vaccination–induced emergency granulopoiesis provides rapid protection from neonatal sepsis." Science Translational Medicine 12, no. 542 (May 6, 2020): eaax4517. http://dx.doi.org/10.1126/scitranslmed.aax4517.

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Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.

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Kimura, Akiko, Michael A. Rieger, James M. Simone, Weiping Chen, Mark C. Wickre, Bing-Mei Zhu, Philipp S. Hoppe, John J. O'Shea, Timm Schroeder, and Lothar Hennighausen. "The transcription factors STAT5A/B regulate GM-CSF–mediated granulopoiesis." Blood 114, no. 21 (November 19, 2009): 4721–28. http://dx.doi.org/10.1182/blood-2009-04-216390.

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Abstract Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with complete deletion of both Stat5a/b genes in hematopoietic cells. In homeostasis, peripheral neutrophils were markedly decreased in these animals. Moreover, during emergency situations, such as myelosuppression, Stat5a/b-mutant mice failed to produce enhanced levels of neutrophils and were unable to respond to GM-CSF. Both the GM-CSF–permitted survival of mature neutrophils and the generation of granulocytes from granulocyte-macrophage progenitors (GMPs) were markedly reduced in Stat5a/b mutants. GMPs showed impaired colony-formation ability with reduced number and size of colonies on GM-CSF stimulation. Moreover, continuous cell fate analyses by time-lapse microscopy and single cell tracking revealed that Stat5a/b-null GMPs showed both delayed cell-cycle progression and increased cell death. Finally, transcriptome analysis indicated that STAT5A/B directs GM-CSF signaling through the regulation of proliferation and survival genes.

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Pedersen, Corinna C., Rehannah Borup, Anne Fischer-Nielsen, Helena Mora-Jensen, Anna Fossum, Jack B. Cowland, and Niels Borregaard. "Changes in Gene Expression during G-CSF–Induced Emergency Granulopoiesis in Humans." Journal of Immunology 197, no. 5 (August 1, 2016): 1989–99. http://dx.doi.org/10.4049/jimmunol.1502690.

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30

Kreisel, Daniel, Seiichiro Sugimoto, Jeremy Tietjens, Jihong Zhu, Sumiharu Yamamoto, Alexander S. Krupnick, Ruaidhri J. Carmody, and Andrew E. Gelman. "Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis." Journal of Clinical Investigation 121, no. 1 (January 4, 2011): 265–76. http://dx.doi.org/10.1172/jci42596.

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31

Basu, Sunanda, George Hodgson, Hui-Hua Zhang, Melissa Katz, Cathy Quilici, and Ashley R. Dunn. "“Emergency” granulopoiesis in G-CSF–deficient mice in response to Candida albicans infection." Blood 95, no. 12 (June 15, 2000): 3725–33. http://dx.doi.org/10.1182/blood.v95.12.3725.

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Abstract Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein believed to play an important role in regulating granulopoiesis both at steady state and during an “emergency” situation. Generation of G-CSF and G-CSF receptor–deficient mice by gene targeting has demonstrated unequivocally the importance of G-CSF in the regulation of baseline granulopoiesis. This study attempted to define the physiologic role of G-CSF during an emergency situation by challenging a cohort of wild-type and G-CSF–deficient mice with Candida albicans. Interestingly, after infection, G-CSF–deficient mice developed an absolute neutrophilia that was observed both in blood and bone marrow. In addition, 3 days after Candida infection increased numbers of granulocyte-macrophage (GM) and macrophage (M) progenitors were observed in the bone marrow of G-CSF–deficient mice. Of the cytokines surveyed, interleukin (IL)-6 levels in serum were elevated; interestingly, levels of IL-6 were higher and more sustained in G-CSF–deficient mice infected with C albicans than similarly infected wild-type mice. Despite the higher levels of serum IL-6, this cytokine is dispensable for the observed neutrophilia because candida-infected IL-6–deficient mice, or mice simultaneously deficient in G-CSF and IL-6, developed neutrophilia. Similarly, mice lacking both G-CSF and GM-CSF developed absolute neutrophilia and had elevated numbers of GM and M progenitors in the bone marrow; thus, G-CSF and GM-CSF are dispensable for promoting the emergency response to candidal infection.

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Basu, Sunanda, George Hodgson, Hui-Hua Zhang, Melissa Katz, Cathy Quilici, and Ashley R. Dunn. "“Emergency” granulopoiesis in G-CSF–deficient mice in response to Candida albicans infection." Blood 95, no. 12 (June 15, 2000): 3725–33. http://dx.doi.org/10.1182/blood.v95.12.3725.012k06_3725_3733.

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Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein believed to play an important role in regulating granulopoiesis both at steady state and during an “emergency” situation. Generation of G-CSF and G-CSF receptor–deficient mice by gene targeting has demonstrated unequivocally the importance of G-CSF in the regulation of baseline granulopoiesis. This study attempted to define the physiologic role of G-CSF during an emergency situation by challenging a cohort of wild-type and G-CSF–deficient mice with Candida albicans. Interestingly, after infection, G-CSF–deficient mice developed an absolute neutrophilia that was observed both in blood and bone marrow. In addition, 3 days after Candida infection increased numbers of granulocyte-macrophage (GM) and macrophage (M) progenitors were observed in the bone marrow of G-CSF–deficient mice. Of the cytokines surveyed, interleukin (IL)-6 levels in serum were elevated; interestingly, levels of IL-6 were higher and more sustained in G-CSF–deficient mice infected with C albicans than similarly infected wild-type mice. Despite the higher levels of serum IL-6, this cytokine is dispensable for the observed neutrophilia because candida-infected IL-6–deficient mice, or mice simultaneously deficient in G-CSF and IL-6, developed neutrophilia. Similarly, mice lacking both G-CSF and GM-CSF developed absolute neutrophilia and had elevated numbers of GM and M progenitors in the bone marrow; thus, G-CSF and GM-CSF are dispensable for promoting the emergency response to candidal infection.

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Ng, Julie, Fei Guo, Anna E. Marneth, Sailaja Ghanta, Min-Young Kwon, Joshua Keegan, Xiaoli Liu, et al. "Augmenting emergency granulopoiesis with CpG conditioned mesenchymal stromal cells in murine neutropenic sepsis." Blood Advances 4, no. 19 (October 13, 2020): 4965–79. http://dx.doi.org/10.1182/bloodadvances.2020002556.

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Abstract Patients with immune deficiencies from cancers and associated treatments represent a growing population within the intensive care unit with increased risk of morbidity and mortality from sepsis. Mesenchymal stromal cells (MSCs) are an integral part of the hematopoietic niche and express toll-like receptors, making them candidate cells to sense and translate pathogenic signals into an innate immune response. In this study, we demonstrate that MSCs administered therapeutically in a murine model of radiation-associated neutropenia have dual actions to confer a survival benefit in Pseudomonas aeruginosa pneumo-sepsis that is not from improved bacterial clearance. First, MSCs augment the neutrophil response to infection, an effect that is enhanced when MSCs are preconditioned with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist. Using cytometry by time of flight, we identified proliferating neutrophils (Ly6GlowKi-67+) as the main expanded cell population within the bone marrow. Further analysis revealed that CpG-MSCs expand a lineage restricted progenitor population (Lin−Sca1+C-kit+CD150−CD48+) in the bone marrow, which corresponded to a doubling in the myeloid proliferation and differentiation potential in response to infection compared with control. Despite increased neutrophils, no reduction in organ bacterial count was observed between experimental groups. However, the second effect exerted by CpG-MSCs is to attenuate organ damage, particularly in the lungs. Neutrophils obtained from irradiated mice and cocultured with CpG-MSCs had decreased neutrophil extracellular trap formation, which was associated with decreased citrullinated H3 staining in the lungs of mice given CpG-MSCs in vivo. Thus, this preclinical study provides evidence for the therapeutic potential of MSCs in neutropenic sepsis.

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Croker, Ben A., Donald Metcalf, Lorraine Robb, Wei Wei, Sandra Mifsud, Ladina DiRago, Leonie A. Cluse, et al. "SOCS3 Is a Critical Physiological Negative Regulator of G-CSF Signaling and Emergency Granulopoiesis." Immunity 20, no. 2 (February 2004): 153–65. http://dx.doi.org/10.1016/s1074-7613(04)00022-6.

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Wirths, Stefan, Stefanie Bugl, and Hans-Georg Kopp. "Neutrophil homeostasis and its regulation by danger signaling." Blood 123, no. 23 (June 5, 2014): 3563–66. http://dx.doi.org/10.1182/blood-2013-11-516260.

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AbstractHematopoiesis in general is demand driven and adaptive, but in contrast to erythropoiesis or thrombocytopoiesis, our knowledge on how neutrophil production is adapted to individual needs remains incomplete. Recently, neutrophil homeostasis has been shown to depend on danger receptors, macrophages, and even circadian rhythms. Puzzle pieces for a broader view of neutrophil homeostasis accumulate, and we will herein try to put seemingly contradictory evidence in a perspective of neutrophil homeostasis and emergency granulopoiesis determined by innate immunologic signaling.

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Danek, Petr, Miroslava Kardosova, Lucie Janeckova, Vladimir Korinek, Touati Benoukraf, Daniel G. Tenen, and Meritxell Alberich-Jorda. "Β-Catenin-Tcf/Lef Signaling Promotes Steady State and Emergency Granulopoiesis through G-CSF Receptor Upregulation." Blood 134, Supplement_1 (November 13, 2019): 1193. http://dx.doi.org/10.1182/blood-2019-122254.

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The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the Tcf/Lef transcription factors and subsequent transcriptional activation of Wnt-target genes. This pathway acts as an essential regulator of differentiation and cell fate decisions in various tissues. In the hematopoietic system, the function of the pathway has been investigated mainly by genetic manipulation of β-catenin. However, this approach does not allow to discriminate between Tcf/Lef dependent or independent β-catenin activity. In order to specifically identify the function of β-catenin-Tcf/Lef signaling in hematopoietic cells, we employed a transgenic mouse model expressing a dominant negative form of the human TCF4 transcription factor (dnTCF4). dnTCF4, a truncated protein lacking the β-catenin binding domain, abrogates activation of Wnt target genes, even when β-catenin is stabilized and translocated into the nucleus. In our model, expression of dnTCF4 is activated from the Rosa26 locus only in cells producing Cre recombinase (driven by Vav-iCre). Importantly, all components of Wnt signaling, including endogenous Tcf/Lef proteins and β-catenin, are intact in Cre-expressing cells. We observed that dnTCF4 transgenic mice have reduced numbers of granulocytes together with accumulation of short-term hematopoietic stem cells (ST-HSC) and common myeloid progenitors (CMPs) in bone marrow. Accordingly, dnTCF4-expressing bone marrow consistently showed a block of granulocytic differentiation and retention of an immature phenotype in colony forming assays. This differentiation arrest and accumulation of immature cells was also observed when wild type cells were cultured in semi-solid medium in the presence of a cell-penetrating peptide that disrupts β-catenin-Tcf/Lef interaction. Together, these results indicate that disruption of the β-catenin/Tcf-Lef interaction, either by genetic manipulation or a drug based approach, alters steady-state hematopoiesis. To identify a mechanism through which β-catenin-Tcf/Lef signaling affects granulopoiesis, wild type and dnTCF4 expressing ST-HSCs were subjected to RNA sequencing. Several genes related to myeloid development were differentially expressed in dnTCF4 expressing cells, including downregulation of Csf3r, the gene encoding for the G-CSF receptor. Publicly available datasets from ChIP-seq experiments on human cell lines confirmed TCF4 enrichment in the distal promoter of the CSF3R gene, suggesting that CSF3R is directly regulated by canonical Wnt signaling. Using flow cytometry we verified reduced levels of G-CSF receptor on the cell surface of dnTCF4 progenitor cells, and attenuation of downstream Stat3 phosphorylation after G-CSF treatment. Finally, when grown in the presence of G-CSF, dnTCF4-expressing bone marrow cells showed impaired differentiation abilities and reduced granulocytic counts compared to wild type bone marrow cells. These results encouraged us to investigate the role of the β-catenin-Tcf/Lef signaling pathway during emergency granulopoiesis by challenging mice with lipopolysaccharide (LPS). Remarkably, dnTCF4 mice showed defects upon LPS stimulation, and completely failed to maintain and expand myeloid progenitor populations, a critical step during emergency granulopoiesis. Altogether, we showed that β-catenin-Tcf/Lef signaling axis is crucial for proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Mechanistically, we demonstrated that the β-catenin-Tcf/Lef interaction controls expression of genes involved in myeloid differentiation, and directly enhances expression of the G-CSF receptor, a crucial molecule for proper development of granulocytes. Disclosures No relevant conflicts of interest to declare.

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Kim, Hyung Sik, Min Young Park, Sung Kyun Lee, Joon Seong Park, Ha Young Lee, and Yoe-Sik Bae. "Activation of formyl peptide receptor 2 by WKYMVm enhances emergency granulopoiesis through phospholipase C activity." BMB Reports 51, no. 8 (August 31, 2018): 418–23. http://dx.doi.org/10.5483/bmbrep.2018.51.8.080.

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Hu, Liping, Weiqi Huang, Elizabeth E. Hjort, Ling Bei, Leonidas C. Platanias, and Elizabeth A. Eklund. "The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis." Journal of Biological Chemistry 291, no. 8 (December 18, 2015): 4107–20. http://dx.doi.org/10.1074/jbc.m115.681361.

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39

Hayashi, Yoshihiro, Hideyo Hirai, Hisayuki Yao, Satoshi Yoshioka, Sakiko Satake, Naoka Kamio, Yasuo Miura, et al. "BCR/ABL-Mediated Myeloid Expansion Is Promoted by C/EBPβ, a Regulator of Emergency Granulopoiesis,." Blood 118, no. 21 (November 18, 2011): 3747. http://dx.doi.org/10.1182/blood.v118.21.3747.3747.

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Abstract Abstract 3747 Chronic phase chronic myeloid leukemia (CP-CML) is characterized by the increase of myeloid cells in the peripheral blood (PB) and bone marrow (BM). We have previously shown that the C/EBPβ transcription factor is required for emergency granulopoiesis, increased proliferation and differentiation of granulocytic precursors in emergency situations such as infection (Hirai H et al., Nature Immunol. 2006). Enhanced myelopoiesis is a common feature between emergency situations and CP-CML. However, little is known about the roles of C/EBPβ in the pathogenesis of CP-CML. The aim of this study is to elucidate the regulation and function of C/EBPβ in BCR/ABL-mediated myeloid expansion. We first assessed the expression level of C/EBPβ in hematopoietic stem cells and myeloid progenitors in BM obtained from healthy donors or CP-CML patients. The transcript of C/EBPβ is expressed at significantly higher level in common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in CP-CML BM than those in normal BM. When BCR/ABL was retrovirally transduced into a mouse hematopoietic stem cell line, EML, C/EBPβ expression was significantly upregulated. Treatment of the EML-BCR/ABL cells with imatinib mesylate normalized the expression level of C/EBPβ. These data suggested that C/EBPβ was upregulated in response to the downstream signaling of BCR/ABL. In order to investigate the function of C/EBPβ in BCR/ABL-mediated myeloid expansion, BCR/ABL was retrovirally introduced into BM cells obtained from 5-FU treated C/EBPβ knockout (KO) mice and their properties were compared with those of BCR/ABL-transduced BM cells from wild type (WT) mice. When the transduced cells were cultured in cytokine-free semisolid methylcellulose medium, the number and the size of the colonies of C/EBPβ KO cells were significantly smaller. Flow cytometric analysis of the colony-forming cells revealed that the BCR/ABL-transduced C/EBPβ KO BM cells gave rise to higher frequency of c-kit+ cells and lower CD11b+ cells than BCR/ABL-transduced WT BM cells (%c-kit+ cells=8.2±3.0% vs. 11.3±3.5%, p=0.002, %CD11b+ cells=75.1±2.1% vs. 90.0±4.2%, p=0.003). In addition, BCR/ABL-transduced C/EBPβ KO BM cells revealed higher replating efficiency than BCR/ABL-transduced WT BM cells. To investigate the role of C/EBPβ in leukemogenesis, BCR/ABL-transduced BM cells from C/EBPβ KO mice or WT mice were transplanted into lethally irradiated recipient mice. In mice transplanted with BCR/ABL-transduced C/EBPβ KO cells, the increase of white blood cell count was delayed (Figure) and higher frequency of c-kit+ cells were observed in the BM at day 19 post transplantation (16.0±2.6% vs. 5.5±4.6%, p=0.01). Spleen size of mice transplanted with BCR/ABL-transduced WT cells is much larger than that of BCR/ABL-transduced C/EBPβ KO cells (Figure). The median survival of mice transplanted with BCR/ABL-transduced WT cells was 19 days. In contrast, the median survival of mice transplanted with BCR/ABL-transduced C/EBPβ KO cells was 31 days (p=0.0005). In summary, C/EBPβ is upregulated by BCR/ABL and the absence of C/EBPβ resulted in delayed proliferation and differentiation of myeloid cells both in vitro and in vivo. Our results suggest that C/EBPβ is involved in the BCR/ABL-mediated myeloid expansion in CP-CML and that C/EBPβ can be the novel molecular target for the therapy of CML. We are currently investigating the molecular mechanisms which mediate the upregulation of C/EBPβ and the direct targets of C/EBPβ in CP-CML. Disclosures: No relevant conflicts of interest to declare.

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Danek, Petr, Miroslava Kardosova, Lucie Janeckova, Elena Karkoulia, Karolina Vanickova, Matej Fabisik, Carlos Lozano-Asencio, et al. "β-Catenin–TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation." Blood 136, no. 22 (November 26, 2020): 2574–87. http://dx.doi.org/10.1182/blood.2019004664.

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Abstract The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.

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Keightley, M. Cristina, Duncan P. Carradice, Joly Kwek, Ashley Buckle, Judith E. Layton, Joan K. Heath, and Graham J. Lieschke. "Zbtb11, an Evolutionarily Conserved Pu.1-Regulated Transcriptional Repressor of TP53, Is Required for Neutrophil Development." Blood 126, no. 23 (December 3, 2015): 1180. http://dx.doi.org/10.1182/blood.v126.23.1180.1180.

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Abstract In response to infection and injury, the hematopoietic system must orchestrate rapid expansion of the neutrophil population. Maintaining this high number of short-lived cells and rapidly increasing their supply on demand requires tightly coordinated but flexible regulation. Neutrophils derive from a common myeloid progenitor that can also give rise to macrophages. Although transcriptional mechanisms have been identified that influence the balance of neutrophil or macrophage production from this common progenitor, the exact pathways governing the relative preponderance of neutrophils and macrophages in the output remain unknown. Here we identify the transcriptional repressor Zbtb11, describe its requirement for neutrophil but not macrophage development, and establish Zbtb11-dependent regulation of TP53 as a new functional pathway instructing neutrophil lineage development. We identified the requirement for Zbtb11 in myeloid development by forward genetics and characterizing a resultant temperature-sensitive Zbtb11-deficient mutant, marsanne (mne). Zbtb11 is a little-studied transcriptional repressor of the BTBZF transcription factor family (which includes PLZF and BCL6). Zbtb11 shows enriched expression in myeloid precursors. Its deficiency leads to a pleiotropic phenotype including abnormally few neutrophils. Demand-driven granulopoiesis is obtunded in mne whether stimulated by Csf3a (G-CSF) or microorganisms. Normalizing basal granulopoiesis in mne by temperature shift did not restore emergency granulopoietic capacity. Hence, there is also a strong genetic requirement for Zbtb11 in emergency granulopoiesis. The genetic requirement in myelopoiesis for Zbtb11 is neutrophil lineage specific, since macrophage numbers are normal in mne and repopulation of macrophages following ablation occurs regardless of Zbtb11 sufficiency/deficiency. In luciferase assays, the Zbtb11 promoter is regulated by master myeloid transcription factors, including Pu.1, C/ebp-a, and Gfi1, positioning Zbtb11 directly within myeloid transcriptional networks. Microarray analysis of mne embryos revealed enrichment of pro-apoptotic genes including tp53 and bbc3 (Puma), known for its importance in hematopoietic cells. Zbtb11 directly represses the TP53 promoter in a luciferase assay and targets the TP53 locus by chromatin immunoprecipitation in K562 cells, suggesting the high tp53 levels in mne are at least, in part, a functional consequence of tp53 derepression by loss of Zbtb11 repressor function. The mne mutationis a T>A transversion causing a Cys116>Ser substitution in the N-terminal domain of Zbtb11. The region surrounding this mutation has been regarded as devoid of any known protein structural motif. However, cross-species homology analysis identified a conserved C2H2 configuration shared with a viral integrase that includes the Cys116 in the N-terminal domain that is mutated in mne. In structure/function studies using phenotypic rescue of mne as an in vivo functional bioassay, mRNAs with mutations in each His/Cys residue showed compromised Zbtb11 function. Ability to rescue was further compromised by mutation of all four conserved residues but not mutation of non-conserved Gln98. Furthermore, the C116S mutation disables Zbtb11 regulation of the TP53 promoter. We propose that the C116S mutation compromises Zbtb11 function by disrupting a novel zinc finger structure identified by modeling the N-terminal of the protein, in which Cys116 directly contacts the central metal cation. Ongoing studies are exploring this pathway further. ChIPseq in human K562 cells is determining genome wide downstream targets of ZBTB11 in hematopoietic cells. RNAseq transcriptional profiling of Zbtb11-deficient compared to WT neutrophils is further delineating precisely where and how the block in mne granulopoiesis occurs and identifying the required Zbtb11-integrated genetic pathways. These studies are supported by ongoing analysis and characterization of a Zbtb11 conditional knockout mouse. These data provide genetic, biochemical and functional evidence identifying a Pu.1-Zbtb11-tp53 pathway as a new mechanism regulating the output of myelopoiesis. Collectively, the in vivo zebrafish genetic and phenotypic data and the concordant mammalian and zebrafish biochemical data underscore the evolutionary conservation of Zbtb11 function in this pathway. Disclosures No relevant conflicts of interest to declare.

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Satake, Sakiko, Hideyo Hirai, Yoshihiro Hayashi, Nobuaki Shime, Akihiro Tamura, Hisayuki Yao, Satoshi Yoshioka, et al. "C/EBPβ Is Involved in the Amplification of Early Granulocyte Precursors during Candidemia-Induced “Emergency” Granulopoiesis." Journal of Immunology 189, no. 9 (September 28, 2012): 4546–55. http://dx.doi.org/10.4049/jimmunol.1103007.

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Kwak, Hyun-Jeong, Peng Liu, Besnik Bajrami, Yuanfu Xu, Shin-Young Park, César Nombela-Arrieta, Subhanjan Mondal, et al. "Myeloid Cell-Derived Reactive Oxygen Species Externally Regulate the Proliferation of Myeloid Progenitors in Emergency Granulopoiesis." Immunity 42, no. 1 (January 2015): 159–71. http://dx.doi.org/10.1016/j.immuni.2014.12.017.

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Märklin, Melanie, Stefanie Bugl, Stefan Wirths, Julia-Stefanie Frick, Martin R. Müller, Hans-Georg Kopp, and Dominik Schneidawind. "Oral intake of lipopolysaccharide regulates toll-like receptor 4-dependent granulopoiesis." Experimental Biology and Medicine 245, no. 14 (June 9, 2020): 1254–59. http://dx.doi.org/10.1177/1535370220931043.

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While neutrophil production in emergency states has been extensively studied, regulation of neutrophil homeostasis in the steady-state remained incompletely understood. We have shown that innate immune receptor toll-like receptor (TLR)4 and downstream TIR-domain-containing adapter-inducing interferon-β (TRIF) are indispensable for the generation of a granulocyte-colony stimulating factor (G-CSF)-dependent regulatory feedback loop upon antibody-induced neutropenia. These findings demonstrated that steady-state granulopoiesis is a demand-driven process, which may rely on differential triggering of innate immune receptors by microbial cell wall constituents such as lipopolysaccharide. Herein, we present further evidence on underlying mechanisms: oral intake of highly endotoxic lipopolysaccharide, but not TLR-antagonistic lipopolysaccharide derived from Rhodobacter sphaeroides, induces hematopoietic stem and progenitor cell fate decisions toward the neutrophil lineage independent of G-CSF. TLR4 has been identified as the indispensable sensor for oral lipopolysaccharide-modulated steady-state granulopoiesis. These results have important implications: food lipopolysaccharide content or the composition of the gastrointestinal microbiome may be strongly underrated as determinants of peripheral blood neutrophil levels. Both neutrophilia and neutropenia are associated with drastically worse outcomes in epidemiological studies of the general population as well as in diseased states. Impact statement In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.

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Zhan, Yifan, Graham J. Lieschke, Dianne Grail, Ashley R. Dunn, and Christina Cheers. "Essential Roles for Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and G-CSF in the Sustained Hematopoietic Response ofListeria monocytogenes–Infected Mice." Blood 91, no. 3 (February 1, 1998): 863–69. http://dx.doi.org/10.1182/blood.v91.3.863.

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Abstract The in vivo roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte (G)-CSF were studied in factor-deficient gene-targeted knockout mice infected with the facultative intracellular bacterium Listeria monocytogenes.Previous results showed that G-CSF−/− mice had an underlying selective deficiency in granulopoiesis, but GM-CSF−/− mice had little disturbance in resting hematopoiesis. Nevertheless, in this study it is revealed that 3 days after intraperitoneal infection with 2 × 105Listeria, GM-CSF−/− mice harbored 50-fold more organisms in their spleen and liver than similarly infected wild-type mice. This was accompanied by a severe depletion of bone marrow hematopoietic cells and a deficient inflammatory response in their peritoneal cavity. Thus, GM-CSF is essential for emergency, but not resting, hematopoiesis. In contrast, G-CSF−/− mice were markedly susceptible to low doses (2 × 104) ofListeria intraperitoneally. After infection, the acute (1 day) granulocyte infiltration to the peritoneal cavity was normal compared with wild type, but the more prolonged monocyte response was deficient, reflecting a continued decrease in bone marrow cellularity and hematopoiesis over 3 days, which was not observed in infected wild-type mice. It is thus apparent that G-CSF deficiency affects monocytopoiesis as well as granulopoiesis during infection.

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46

Zhan, Yifan, Graham J. Lieschke, Dianne Grail, Ashley R. Dunn, and Christina Cheers. "Essential Roles for Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and G-CSF in the Sustained Hematopoietic Response ofListeria monocytogenes–Infected Mice." Blood 91, no. 3 (February 1, 1998): 863–69. http://dx.doi.org/10.1182/blood.v91.3.863.863_863_869.

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The in vivo roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte (G)-CSF were studied in factor-deficient gene-targeted knockout mice infected with the facultative intracellular bacterium Listeria monocytogenes.Previous results showed that G-CSF−/− mice had an underlying selective deficiency in granulopoiesis, but GM-CSF−/− mice had little disturbance in resting hematopoiesis. Nevertheless, in this study it is revealed that 3 days after intraperitoneal infection with 2 × 105Listeria, GM-CSF−/− mice harbored 50-fold more organisms in their spleen and liver than similarly infected wild-type mice. This was accompanied by a severe depletion of bone marrow hematopoietic cells and a deficient inflammatory response in their peritoneal cavity. Thus, GM-CSF is essential for emergency, but not resting, hematopoiesis. In contrast, G-CSF−/− mice were markedly susceptible to low doses (2 × 104) ofListeria intraperitoneally. After infection, the acute (1 day) granulocyte infiltration to the peritoneal cavity was normal compared with wild type, but the more prolonged monocyte response was deficient, reflecting a continued decrease in bone marrow cellularity and hematopoiesis over 3 days, which was not observed in infected wild-type mice. It is thus apparent that G-CSF deficiency affects monocytopoiesis as well as granulopoiesis during infection.

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Herrera, Matias, Susana Salva, Julio Villena, Natalia Barbieri, Gabriela Marranzino, and Susana Alvarez. "Dietary Supplementation with Lactobacilli Improves Emergency Granulopoiesis in Protein-Malnourished Mice and Enhances Respiratory Innate Immune Response." PLoS ONE 9, no. 4 (April 1, 2014): e90227. http://dx.doi.org/10.1371/journal.pone.0090227.

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Shah, Chirag A., Larisa Broglie, Liping Hu, Ling Bei, Weiqi Huang, Danielle B. Dressler, and Elizabeth A. Eklund. "Stat3 and CCAAT enhancer–binding protein β (C/ebpβ) activate Fanconi C gene transcription during emergency granulopoiesis." Journal of Biological Chemistry 293, no. 11 (January 30, 2018): 3937–48. http://dx.doi.org/10.1074/jbc.ra117.000528.

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Knackstedt, Sebastian Lorenz, Athina Georgiadou, Falko Apel, Ulrike Abu-Abed, Christopher A. Moxon, Aubrey J. Cunnington, Bärbel Raupach, et al. "Neutrophil extracellular traps drive inflammatory pathogenesis in malaria." Science Immunology 4, no. 40 (October 18, 2019): eaaw0336. http://dx.doi.org/10.1126/sciimmunol.aaw0336.

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Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule–1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.

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Cain, Derek, Yoshihiro Ueda, Thomas Holl, Pilar Snowden, Motonari Kondo, and Garnett Kelsoe. "T.20. Evidence for a Single Pathway of Neutrophil Production to Explain Both “Steady-state” and “Emergency” Granulopoiesis." Clinical Immunology 131 (2009): S56—S57. http://dx.doi.org/10.1016/j.clim.2009.03.161.

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Journal articles on the topic 'Emergency granulopoiesis'

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