title: Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis.
abstract: 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.
authors.affiliation: Herman B Wells Center, Indiana University Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Boyan
authors.initials: B
authors.lastname: Goumnerov
authors.forename: Christen
authors.initials: C
authors.lastname: Mumaw
authors.forename: W Scott
authors.initials: WS
authors.lastname: Goebel
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Hasan
authors.initials: H
authors.lastname: Baydoun
authors.forename: Harm
authors.initials: H
authors.lastname: HogenEsch
authors.forename: David M
authors.initials: DM
authors.lastname: Dombkowski
authors.forename: Carol A
authors.initials: CA
authors.lastname: Karlewicz
authors.forename: Susan
authors.initials: S
authors.lastname: Rice
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology*; D009503:Neutropenia / Q000209:etiology / Q000276:immunology / Q000473:pathology; D011552:Pseudomonas Infections / Q000150:complications / Q000276:immunology / Q000473:pathology; D018805:Sepsis / Q000150:complications / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
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