Clostridium perfringens ?-toxin impairs granulocyte colony-stimulating factor receptor-mediated granulocyte production while triggering septic shock.

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 ?-toxin impairs granulopoiesis via an unknown mechanism. Here, we tested whether G-CSF accounts for the ?-toxin-mediated impairment of granulopoiesis. We find that ?-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, ?-toxin inhibits G-CSF-mediated cell proliferation of Ly-6G+ neutrophils by inducing degradation of G-CSF receptor (G-CSFR). During sepsis, administration of ?-toxin promotes lethality and tissue injury accompanied by accelerated production of inflammatory cytokines in a TLR4-dependent manner. Together, our results illustrate that ?-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.

SUBMITTER: Takehara M 

PROVIDER: S-EPMC6355902 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature