Acute alcohol intoxication impairs SHH-GLI1 signaling and activation of primitive hematopoietic precursor cells in the early stage of host response to bacteremia.

Acute alcohol intoxication impairs SHH-GLI1 signaling and activation of primitive hematopoietic precursor cells in the early stage of host response to bacteremia.

Shi X; Simms KJ; Zhang P

Alcoholism, Clinical and Experimental Research

2020

2020-08-09

BACKGROUND: Activation of hematopoietic stem cells [HSCs, lineage(lin)(-) stem cell growth factor receptor(c-kit)(+) stem cell antigen-1(Sca-1)(+) or LKS cells in mice], is critical for initiating the granulopoietic response. This study determined the effect of alcohol exposure on sonic hedgehog (SHH) signaling in the regulation of HSC activation during bacteremia. METHODS: Acute alcohol intoxication was induced in mice by intraperitoneal (i.p.) injection of 20% alcohol (5 g alcohol/kg body weight). Control mice received i.p. saline. Thirty minutes later, mice were intravenously (i.v.) injected with Escherichia coli (E. coli, 1 - 5 x 10(7) CFUs/mouse) or saline. RESULTS: SHH expression by lineage negative bone marrow cells (BMCs) was significantly increased 24 h after E. coli infection. Extracellular signal-regulated kinase 1/2 (ERK1/2)-specificity protein 1 (Sp1) signaling promotes SHH expression. ERK1/2 was markedly activated in BMCs 8 h following E. coli infection. Alcohol suppressed both the activation of ERK1/2 and up-regulation of SHH expression following E. coli infection. E. coli infection up-regulated GLI family zinc finger 1 (Gli1) gene expression by BMCs and increased Gli1 protein content in LKS cells. The extent of Gli1 expression was correlated with the activity of proliferation in LKS cells. Alcohol inhibited up-regulation of Gli1 expression and activation of LKS cells in response to E. coli infection. Alcohol also interrupted the granulopoietic response to bacteremia. CONCLUSION: These data show that alcohol disrupts SHH-Gli1 signaling and HSC activation in the early stage of the granulopoietic response, which may serve as an important mechanism underlying the impairment of immune defense against bacterial infection in host excessively consuming alcohol.

bacteremia; alcohol; hematopoietic stem cells; host response; sonic hedgehog

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journalArticle

1530-0277 0145-6008

NEOMED College of Medicine

Department of Integrative Medical Sciences

August 2020 List