A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis

摘要: Although Gram-positive infections account for the majority of cases sepsis, molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components bacteria contribute to development sepsis. Experimental observations derived from cultured primary macrophages and line indicate that bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA protein expression. Inoculation live or heat-inactivated with induced HIF-1 transcriptional activity in macrophages. Concordant these results, myeloid deficiency HIF-1α attenuated endotoxin-induced cellular motility proinflammatory gene expression Conversely, reduced anti-inflammatory transcription Kruppel-like 2 (KLF2). Sustained KLF2 enhanced More importantly, cells. Consistent mice deficient were protected sepsis mortality clinical symptomatology. By contrast, KLF2-deficient susceptible symptoms. Collectively, identify as critical regulators endotoxin-mediated