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

作者：Shi Xin; Siggins Robert W; Stanford William L; Melvan John N; Basson Marc D; Zhang Ping^*

来源：Infection and Immunity, 2013, 81(6): 2197-2205.

DOI：10.1128/IAI.01280-12

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.

• 出版日期2013-6