Emergency granulopoiesis

Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.

[1]  A. Lanzavecchia,et al.  Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon–producing and dendritic cell development , 2006, The Journal of experimental medicine.

[2]  D. Metcalf.  Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation. , 1998, Blood.

[3]  Sarah C Mullaly,et al.  Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. , 2003, The Journal of clinical investigation.

[4]  Irving L Weissman,et al.  Biology of hematopoietic stem cells and progenitors: implications for clinical application. , 2003, Annual review of immunology.

[5]  Pu Zhang,et al.  Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. , 2004, Immunity.

[6]  R. Ye,et al.  Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. , 2009, Blood.

[7]  I. Weissman,et al.  Lineage infidelity in myeloid cells with TCR gene rearrangement: A latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Scheidereit,et al.  Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-κB , 1992, Nature.

[9]  J. Armitage,et al.  Colony-stimulating factors for febrile neutropenia during cancer therapy. , 2013, The New England journal of medicine.

[10]  A. Dunn,et al.  Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Sioud,et al.  TLR agonists induce the differentiation of human bone marrow CD34+ progenitors into CD11c+ CD80/86+ DC capable of inducing a Th1‐type response , 2007, European journal of immunology.

[12]  L. Harker,et al.  Neutrophil kinetics in man. , 1976, The Journal of clinical investigation.

[13]  H. Rammensee,et al.  Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling. , 2013, Blood.

[14]  D. W. Maher,et al.  Differential alterations in plasma colony‐stimulating factor concentrations in meningococcaemia , 1995, Clinical and experimental immunology.

[15]  Nathan C Boles,et al.  Quiescent hematopoietic stem cells are activated by IFNγ in response to chronic infection , 2010, Nature.

[16]  G. Kelsoe,et al.  Inflammation Triggers Emergency Granulopoiesis through a Density-Dependent Feedback Mechanism , 2011, PloS one.

[17]  I. Weissman,et al.  Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines , 2000, Nature.

[18]  H. Hammad,et al.  House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells , 2009, Nature Medicine.

[19]  F. Ginhoux,et al.  Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. , 2013, Immunity.

[20]  W. Alexander,et al.  The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo. , 2007, Blood.

[21]  A. Kelso,et al.  Production of colony-stimulating factors (CSFs) during infection: separate determinations of macrophage-, granulocyte-, granulocyte-macrophage-, and multi-CSFs , 1988, Infection and immunity.

[22]  Yang Liu,et al.  Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice. , 2010, The Journal of clinical investigation.

[23]  T. Shimazu,et al.  Changes in granulocyte colony-stimulating factor concentration in patients with trauma and sepsis. , 1996, The Journal of trauma.

[24]  T. Kumakawa,et al.  Levels of serum granulocyte colony-stimulating factor in patients with infections. , 1990, Blood.

[25]  Satoshi Tanaka,et al.  Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML , 2010, Nature Biotechnology.

[26]  S. Morrison,et al.  Supplemental Experimental Procedures , 2022 .

[27]  M. Pevsner-Fischer,et al.  Toll-like receptors and their ligands control mesenchymal stem cell functions. , 2007, Blood.

[28]  J. Gabrilove,et al.  Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. , 1989, The New England journal of medicine.

[29]  E. Vellenga,et al.  Independent regulation of M-CSF and G-CSF gene expression in human monocytes. , 1988, Blood.

[30]  S. Nutt,et al.  M-CSF instructs myeloid lineage fate in single haematopoietic stem cells , 2013, Nature.

[31]  G. Kelsoe,et al.  IL-1R Type I-Dependent Hemopoietic Stem Cell Proliferation Is Necessary for Inflammatory Granulopoiesis and Reactive Neutrophilia1 , 2009, The Journal of Immunology.

[32]  J. Cebon,et al.  Endogenous haemopoietic growth factors in neutropenia and infection , 1994, British journal of haematology.

[33]  J. Rasko,et al.  Cytokine receptor expression on hematopoietic stem and progenitor cells. , 1997, Blood.

[34]  N. Harris,et al.  MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. , 2012, The New England journal of medicine.

[35]  Philipp S. Hoppe,et al.  The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis. , 2009, Blood.

[36]  S. Akira,et al.  IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-α production in macrophages , 2003 .

[37]  M. Goldsmith,et al.  STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils. , 2006, Blood.

[38]  D. Scadden,et al.  The bone marrow at the crossroads of blood and immunity , 2011, Nature Reviews Immunology.

[39]  D. Link,et al.  STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. , 2001, Immunity.

[40]  A. Miyajima,et al.  Interleukin‐3, granulocyte‐macrophage colony‐stimulating factor, and interleukin‐5 transduce signals through two forms of STAT5 , 1995, Journal of leukocyte biology.

[41]  R. Carmody,et al.  Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade , 2007, Science.

[42]  J. Hamilton.  Colony-stimulating factors in inflammation and autoimmunity , 2008, Nature Reviews Immunology.

[43]  Andreas Trumpp,et al.  IFNα activates dormant haematopoietic stem cells in vivo , 2009, Nature.

[44]  G. Kelsoe,et al.  Inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow , 2005, The Journal of experimental medicine.

[45]  S. Hultgren,et al.  Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Lina A. Thoren,et al.  Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential A Revised Road Map for Adult Blood Lineage Commitment , 2005, Cell.

[47]  Triona Goode,et al.  C/EBPα Arrests Cell Proliferation through Direct Inhibition of Cdk2 and Cdk4 , 2001 .

[48]  J. Taylor‐Papadimitriou,et al.  Implications for clinical application of new developments in interferon research. , 1982, Biochimica et biophysica acta.

[49]  P. Ingham,et al.  Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. , 2011, Blood.

[50]  M. Manz,et al.  Demand-adapted regulation of early hematopoiesis in infection and inflammation. , 2012, Blood.

[51]  A R Dunn,et al.  Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. , 1994, Blood.

[52]  K. Kaushansky,et al.  Lineage-specific hematopoietic growth factors. , 2006, The New England journal of medicine.

[53]  V. Poli,et al.  Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans , 1996, The Journal of experimental medicine.

[54]  L. Pasqualucci.  Diffuse Large B-Cell Lymphoma , 2013 .

[55]  D. Kuter,et al.  The physiological response of thrombopoietin (c‐Mpl ligand) to thrombocytopenia in the rat , 1999, British journal of haematology.

[56]  P. Kubes,et al.  Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection. , 2009, The Journal of clinical investigation.

[57]  R. Cuthbertson,et al.  Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage , 1987, Cell.

[58]  W. Alexander,et al.  SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. , 2004, Immunity.

[59]  L. Koenderman,et al.  Lipopolysaccharide and hemorrhagic shock cause systemic inflammation by different mechanisms , 2013, The journal of trauma and acute care surgery.

[60]  T. Hohl,et al.  Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. , 2011, Immunity.

[61]  J. Gasson.  Molecular physiology of granulocyte-macrophage colony-stimulating factor. , 1991, Blood.

[62]  L. Rahme,et al.  Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. , 2009, Blood.

[63]  Peter J. Murray,et al.  Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-101 , 2002, The Journal of Immunology.

[64]  C. Schürch,et al.  Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells. , 2014, Cell stem cell.

[65]  Ulrich H. von Andrian,et al.  Immunosurveillance by Hematopoietic Progenitor Cells Trafficking through Blood, Lymph, and Peripheral Tissues , 2007, Cell.

[66]  D. Welsh,et al.  The Lineage−c‐Kit+Sca‐1+ Cell Response to Escherichia coli Bacteremia in Balb/c Mice , 2008, Stem cells.

[67]  T. Springer,et al.  The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. , 1999, Immunity.

[68]  C. Cheers,et al.  Essential roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF in the sustained hematopoietic response of Listeria monocytogenes-infected mice. , 1998, Blood.

[69]  D. Tenen,et al.  Upregulation of Interleukin 6 and Granulocyte Colony-Stimulating Factor Receptors by Transcription Factor CCAAT Enhancer Binding Protein α (C/EBPα) Is Critical for Granulopoiesis , 1998, The Journal of experimental medicine.

[70]  S. Collins,et al.  Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation. , 2001, Blood.

[71]  F. Lund-Johansen,et al.  Signaling through toll-like receptor 7/8 induces the differentiation of human bone marrow CD34+ progenitor cells along the myeloid lineage. , 2006, Journal of molecular biology.

[72]  P. Meda,et al.  Junctional adhesion molecule-C (JAM-C) regulates polarized neutrophil transendothelial cell migration in vivo , 2011, Nature immunology.

[73]  S. Akira,et al.  Impaired response to GM-CSF and G-CSF, and enhanced apoptosis in C/EBPbeta-deficient hematopoietic cells. , 2008, Blood.

[74]  K. Akashi,et al.  C/EBPβ is required for 'emergency' granulopoiesis , 2006, Nature Immunology.

[75]  M. Heikenwalder,et al.  Cutting Edge: LPS-Induced Emergency Myelopoiesis Depends on TLR4-Expressing Nonhematopoietic Cells , 2012, The Journal of Immunology.

[76]  D. Kreisel,et al.  Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. , 2011, The Journal of clinical investigation.

[77]  S. Nagata,et al.  Regulatory elements responsible for inducible expression of the granulocyte colony-stimulating factor gene in macrophages , 1990, Molecular and cellular biology.

[78]  G. Feldman,et al.  STAT5A-deficient mice demonstrate a defect in granulocyte-macrophage colony-stimulating factor-induced proliferation and gene expression. , 1997, Blood.

[79]  T. Suda,et al.  Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion , 2009, Nature Medicine.

[80]  C. Scheidereit,et al.  The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators , 1999, Oncogene.

[81]  R. Arceci.  Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes , 2011 .

[82]  Irving L. Weissman,et al.  Physiological Migration of Hematopoietic Stem and Progenitor Cells , 2001, Science.

[83]  C. Cheers,et al.  Haemopoiesis in mice genetically lacking granulocyte–macrophage colony stimulating factor during chronic infection with Mycobacterium avium , 2000, Immunology and cell biology.

[84]  C. Figdor,et al.  Interleukin 10 ( EL , . 10 ) Inhibits Cytokine Synthesis by Human Monocytes : An Autoregulatory Role of IL-10 Produced by Monocytes By Ren 6 de , 2003 .

[85]  C. Quilici,et al.  "Emergency" granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. , 2000, Blood.

[86]  Philipp S. Hoppe,et al.  Hematopoietic Cytokines Can Instruct Lineage Choice , 2009, Science.

[87]  J. Johnston,et al.  Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction1 , 2002, The Journal of Immunology.

[88]  G. Kelsoe,et al.  Inflammation Controls B Lymphopoiesis by Regulating Chemokine CXCL12 Expression , 2004, The Journal of experimental medicine.

[89]  T. Golub,et al.  c-Myc Is a Critical Target for C/EBPα in Granulopoiesis , 2001, Molecular and Cellular Biology.

[90]  L. Genestier,et al.  The TLR1/2 agonist PAM3CSK4 instructs commitment of human hematopoietic stem cells to a myeloid cell fate , 2009, Leukemia.

[91]  J. Borghans,et al.  Whatˈs your age again? Determination of human neutrophil half‐lives revisited , 2013, Journal of leukocyte biology.

[92]  A. Wolkoff,et al.  Macrophages specifically regulate the concentration of their own growth factor in the circulation. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[93]  M. Manz,et al.  Bone marrow dendritic cell progenitors sense pathogens via Toll-like receptors and subsequently migrate to inflamed lymph nodes. , 2011, Blood.

[94]  L. Nie,et al.  Chronic Exposure to a TLR Ligand Injures Hematopoietic Stem Cells , 2011, The Journal of Immunology.

[95]  C. Begley,et al.  Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. , 1987, Experimental hematology.

[96]  K. Garrett,et al.  Functional diversity of stem and progenitor cells with B‐lymphopoietic potential , 2010, Immunological reviews.

[97]  M. Manz,et al.  Dendritic cell homeostasis is maintained by nonhematopoietic and T‐cell‐produced Flt3‐ligand in steady state and during immune responses , 2013, European journal of immunology.

[98]  A. D. Panopoulos,et al.  STAT3 controls myeloid progenitor growth during emergency granulopoiesis. , 2010, Blood.

[99]  C. Quilici,et al.  Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. , 1997, Blood.

[100]  D. Link,et al.  Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. , 1996, Immunity.

[101]  W. Nothdurft,et al.  Cytokines and progenitor cells of granulocytopoiesis in peripheral blood of patients with bacterial infections , 1995, Infection and immunity.

[102]  Andreas Trumpp,et al.  Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair , 2008, Cell.

[103]  Daniel G. Tenen,et al.  Transcription factors in myeloid development: balancing differentiation with transformation , 2007, Nature Reviews Immunology.

[104]  R. Skoda,et al.  Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. , 1996, Blood.

[105]  I. Touw,et al.  Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. , 2003, Blood.

[106]  M. Manz,et al.  The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis. , 2009, Blood.

[107]  Ryan M. O’Connell,et al.  Conversion of Danger Signals into Cytokine Signals By Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis , 2014 .

[108]  N. Shime,et al.  C/EBPβ Is Involved in the Amplification of Early Granulocyte Precursors during Candidemia-Induced “Emergency” Granulopoiesis , 2012, The Journal of Immunology.

[109]  D. Tenen,et al.  Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[110]  S. Akira,et al.  Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. , 2006, Immunity.

[111]  D. Jarrossay,et al.  Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow , 2007, Nature Immunology.

[112]  Antony W Burgess,et al.  IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF- and GM-CSF-deficient mice. , 2008, Blood.

[113]  M. Goodell,et al.  Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response , 2011, Nature Reviews Immunology.

[114]  K. Akashi,et al.  Induction of granulocytic differentiation by 2 pathways. , 2002, Blood.

[115]  A. Burgess,et al.  Mice Lacking Three Myeloid Colony-Stimulating Factors (G-CSF, GM-CSF, and M-CSF) Still Produce Macrophages and Granulocytes and Mount an Inflammatory Response in a Sterile Model of Peritonitis1 , 2007, The Journal of Immunology.

[116]  D. Jarrossay,et al.  Clonal Type I Interferon–producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations , 2004, The Journal of experimental medicine.

[117]  John F. Cade,et al.  Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: Relation to disease severity, multiple organ dysfunction, and mortality , 2000, Critical care medicine.

[118]  Y. Bae,et al.  Role of Toll‐Like Receptors on Human Adipose‐Derived Stromal Cells , 2006, Stem cells.

[119]  K. Akashi,et al.  Enforced Granulocyte/Macrophage Colony-stimulating Factor Signals Do Not Support Lymphopoiesis, but Instruct Lymphoid to Myelomonocytic Lineage Conversion , 2003, The Journal of experimental medicine.

[120]  Ruth S. Waterman,et al.  Toll‐Like Receptors on Human Mesenchymal Stem Cells Drive Their Migration and Immunomodulating Responses , 2008, Stem cells.

[121]  W. Alexander,et al.  The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. , 2004, Annual review of immunology.

[122]  Juliane C. Dohm,et al.  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia , 2011, Nature.

[123]  S. Rankin,et al.  Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. , 2003, Immunity.

[124]  S. Asano,et al.  Serum granulocyte colony-stimulating factor levels in healthy volunteers and patients with various disorders as estimated by enzyme immunoassay. , 1989, Blood.

[125]  Joseph M. Connors,et al.  Oncogenically active MYD88 mutations in human lymphoma , 2011, Nature.

[126]  P. Kubes,et al.  Neutrophil recruitment and function in health and inflammation , 2013, Nature Reviews Immunology.

[127]  L. Cosmi,et al.  Toll‐Like Receptors 3 and 4 Are Expressed by Human Bone Marrow‐Derived Mesenchymal Stem Cells and Can Inhibit Their T‐Cell Modulatory Activity by Impairing Notch Signaling , 2008, Stem cells.

[128]  A. Look,et al.  Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish , 2006, Journal of leukocyte biology.