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.
Rodriguez
Sonia
S
Herman B Wells Center, Indiana University Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
Chora
Angelo
A
Goumnerov
Boyan
B
Mumaw
Christen
C
Goebel
W Scott
WS
Fernandez
Luis
L
Baydoun
Hasan
H
HogenEsch
Harm
H
Dombkowski
David M
DM
Karlewicz
Carol A
CA
Rice
Susan
S
Rahme
Laurence G
LG
Carlesso
Nadia
N
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
D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
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