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Acute Alcohol Intoxication Impairs Sonic Hedgehog‐Gli1 Signaling and Activation of Primitive Hematopoietic Precursor Cells in the Early Stage of Host Response to Bacteremia
Author(s) -
Shi Xin,
Simms Kevin J.,
Zhang Ping
Publication year - 2020
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14429
Subject(s) - sonic hedgehog , gli1 , haematopoiesis , stem cell , signal transduction , biology , cancer research , immunology , hedgehog signaling pathway , microbiology and biotechnology
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 to 5 × 10 7 CFUs/mouse) or saline. Results SHH expression by lineage‐negative bone marrow cells (BMCs) was significantly increased 24 hours 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 hours 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.