Abstract
During bacterial infection, granulocyte colony-stimulating factor (G-CSF) is produced and accelerates neutrophil production from their progenitors. This process, termed granulopoiesis, strengthens host defense, but Clostridium perfringens α-toxin impairs granulopoiesis via an unknown mechanism. Here, we tested whether G-CSF accounts for the α-toxin-mediated impairment of granulopoiesis. We find that α-toxin dramatically accelerates G-CSF production from endothelial cells in response to Toll-like receptor 2 (TLR2) agonists through activation of the c-Jun N-terminal kinase (JNK) signaling pathway. Meanwhile, α-toxin inhibits G-CSF-mediated cell proliferation of Ly-6G+ neutrophils by inducing degradation of G-CSF receptor (G-CSFR). During sepsis, administration of α-toxin promotes lethality and tissue injury accompanied by accelerated production of inflammatory cytokines in a TLR4-dependent manner. Together, our results illustrate that α-toxin disturbs G-CSF-mediated granulopoiesis by reducing the expression of G-CSFR on neutrophils while augmenting septic shock due to excess inflammatory cytokine release, which provides a new mechanism to explain how pathogenic bacteria modulate the host immune system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Toxins / toxicity*
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Calcium-Binding Proteins / toxicity*
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Clostridium perfringens / genetics
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Clostridium perfringens / immunology
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Clostridium perfringens / pathogenicity*
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Cytokines / genetics
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Cytokines / immunology
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Disease Models, Animal
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Female
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Gas Gangrene / genetics*
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Gas Gangrene / immunology
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Gas Gangrene / microbiology
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Gas Gangrene / mortality
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Gene Expression Regulation
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Granulocyte Colony-Stimulating Factor / genetics*
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Granulocyte Colony-Stimulating Factor / immunology
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Hematopoiesis / drug effects
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Hematopoiesis / genetics
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Hematopoiesis / immunology
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / immunology
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Lipopolysaccharides / toxicity*
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / microbiology
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Receptors, Granulocyte Colony-Stimulating Factor / genetics*
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Receptors, Granulocyte Colony-Stimulating Factor / immunology
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Shock, Septic / genetics*
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Shock, Septic / immunology
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Shock, Septic / microbiology
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Shock, Septic / mortality
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Signal Transduction
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Survival Analysis
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Type C Phospholipases / toxicity*
Substances
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Bacterial Toxins
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Calcium-Binding Proteins
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Cytokines
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Lipopolysaccharides
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Receptors, Granulocyte Colony-Stimulating Factor
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Granulocyte Colony-Stimulating Factor
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JNK Mitogen-Activated Protein Kinases
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Type C Phospholipases
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alpha toxin, Clostridium perfringens