Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis.

Severe sepsis is one of the leading causes of death worldwide. High mortality rates in sepsis are frequently associated with neutropenia. Despite the central role of neutrophils in innate immunity, the mechanisms causing neutropenia during sepsis remain elusive. Here, we show that neutropenia is caused in part by apoptosis and is sustained by a block of hematopoietic stem cell (HSC) differentiation. Using a sepsis murine model, we found that the human opportunistic bacterial pathogen Pseudomonas aeruginosa caused neutrophil depletion and expansion of the HSC pool in the bone marrow. "Septic" HSCs were significantly impaired in competitive repopulation assays and defective in generating common myeloid progenitors and granulocyte-monocyte progenitors, resulting in lower rates of myeloid differentiation in vitro and in vivo. Delayed myeloid-neutrophil differentiation was further mapped using a lysozyme-green fluorescent protein (GFP) reporter mouse. Pseudomonas's lipopolysaccharide was necessary and sufficient to induce myelosuppresion and required intact TLR4 signaling. Our results establish a previously unrecognized link between HSC regulation and host response in severe sepsis and demonstrate a novel role for TLR4.

[1]  G. Zhu,et al.  B7-H4-deficient mice display augmented neutrophil-mediated innate immunity. , 2009, Blood.

[2]  S. D’Orazio,et al.  Multiple Mechanisms Contribute to the Robust Rapid Gamma Interferon Response by CD8+ T Cells during Listeria monocytogenes Infection , 2009, Infection and Immunity.

[3]  Y. Liu,et al.  p53 regulates hematopoietic stem cell quiescence. , 2009, Cell stem cell.

[4]  Peter A. Ward,et al.  Harmful molecular mechanisms in sepsis , 2008, Nature Reviews Immunology.

[5]  Göran Karlsson,et al.  Signaling pathways governing stem-cell fate. , 2008, Blood.

[6]  A. Sher,et al.  The p47 GTPase Lrg-47 (Irgm1) links host defense and hematopoietic stem cell proliferation. , 2008, Cell stem cell.

[7]  E. Mocarski,et al.  Pathogen subversion of cell-intrinsic innate immunity , 2007, Nature Immunology.

[8]  M. Cybulsky,et al.  Getting to the site of inflammation: the leukocyte adhesion cascade updated , 2007, Nature Reviews Immunology.

[9]  K. Akashi,et al.  [Myeloid lineage commitment from the hematopoietic stem cell]. , 2007, Arerugi = [Allergy].

[10]  L. Moldawer,et al.  MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis , 2007, The Journal of experimental medicine.

[11]  Mauro M Teixeira,et al.  Down-regulation of CXCR2 on neutrophils in severe sepsis is mediated by inducible nitric oxide synthase-derived nitric oxide. , 2007, American journal of respiratory and critical care medicine.

[12]  M. Minden,et al.  Myelodysplastic syndromes: the complexity of stem-cell diseases , 2007, Nature Reviews Cancer.

[13]  D. Rittirsch,et al.  The disconnect between animal models of sepsis and human sepsis , 2007, Journal of leukocyte biology.

[14]  D. Scadden,et al.  The stem-cell niche as an entity of action , 2006, Nature.

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

[16]  Carl Nathan,et al.  Neutrophils and immunity: challenges and opportunities , 2006, Nature Reviews Immunology.

[17]  W. Gordon,et al.  Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation , 2005, The Journal of experimental medicine.

[18]  H. S. Warren,et al.  Bacterial peptidoglycan-associated lipoprotein: a naturally occurring toll-like receptor 2 agonist that is shed into serum and has synergy with lipopolysaccharide. , 2005, The Journal of infectious diseases.

[19]  M. Karin,et al.  Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists , 2004, The Journal of experimental medicine.

[20]  Peter A. Ward,et al.  Novel strategies for the treatment of sepsis , 2003, Nature Medicine.

[21]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[22]  I. Weissman,et al.  Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation. , 2002, Blood.

[23]  Min Ye,et al.  Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. , 2002, Developmental cell.

[24]  R. Gamelli,et al.  Bone marrow stem cell and progenitor response to injury , 2001, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[25]  R. Gamelli,et al.  Myeloid Commitment Shifts Toward Monocytopoiesis After Thermal Injury and Sepsis , 2001, Annals of surgery.

[26]  D. Scadden,et al.  Hematopoietic stem cell quiescence maintained by p21cip1/waf1. , 2000, Science.

[27]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[28]  R. Gamelli,et al.  Mechanisms of neutropenia involving myeloid maturation arrest in burn sepsis. , 1998, Annals of surgery.

[29]  J. Siewert,et al.  Essential Role of Gamma Interferon in Survival of Colon Ascendens Stent Peritonitis, a Novel Murine Model of Abdominal Sepsis , 1998, Infection and Immunity.

[30]  F. Ausubel,et al.  Use of model plant hosts to identify Pseudomonas aeruginosa virulence factors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  F. Ausubel,et al.  Common virulence factors for bacterial pathogenicity in plants and animals. , 1995, Science.

[32]  I. Weissman,et al.  The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. , 1994, Immunity.

[33]  C. Ryan,et al.  A quantitative model of invasive Pseudomonas infection in burn injury. , 1994, The Journal of burn care & rehabilitation.

[34]  Der,et al.  An in vitro limiting-dilution assay of long-term repopulating hematopoietic stem cells in the mouse. , 1989, Blood.

[35]  R. Degowin,et al.  Chronic inflammation impairs hematopoiesis and survival after irradiation. , 1985, The Journal of laboratory and clinical medicine.

[36]  Myriam Alcalay,et al.  Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells , 2009, Nature.

[37]  K. Akashi,et al.  C/EBPbeta is required for 'emergency' granulopoiesis. , 2006, Nature immunology.

[38]  R. Gamelli,et al.  A mouse model of burn wounding and sepsis. , 2003, Methods in molecular medicine.

[39]  T. Graf,et al.  Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. , 2000, Blood.