title: Toll-like receptor 4/stem cell antigen 1 signaling promotes hematopoietic precursor cell commitment to granulocyte development during the granulopoietic response to Escherichia coli bacteremia.
abstract: In response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection of Escherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin(-)) stem cell growth factor receptor-positive (c-kit(+)) Sca-1(-) cells containing primarily common myeloid progenitors were cultured in vitro without or with E. coli lipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin(-) c-kit(+) cells, as reflected by a marked increase in BrdU-negative lin(-) c-kit(+) Sca-1(+) cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked. In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin(-) c-kit(+) Sca-1(-) cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin(-) c-kit(+) Sca-1(-) cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin(-) c-kit(+) Sca-1(-) cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response to E. coli bacteremia.
authors.affiliation: Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Shi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Siggins
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: John N
authors.initials: JN
authors.lastname: Melvan
authors.forename: Marc D
authors.initials: MD
authors.lastname: Basson
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D016470:Bacteremia / Q000473:pathology*; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000473:pathology*; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019009:Proto-Oncogene Proteins c-kit; D048670:MAP Kinase Kinase 4
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