title: A myeloid hypoxia-inducible factor 1α-Krüppel-like factor 2 pathway regulates gram-positive endotoxin-mediated sepsis.
abstract: Although gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that gram-positive bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression. Inoculation of live or heat-inactivated gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1α attenuated gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced gram-positive endotoxins induced HIF-1α mRNA and protein expression in macrophages. More importantly, KLF2 attenuated gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1α were protected from gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1α and KLF2 as critical regulators of gram-positive endotoxin-mediated sepsis.
authors: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA. ghm4@case.edu
authors: Ganapati H
authors: GH
authors: Mahabeleshwar
authors: Muhammad Awais
authors: MA
authors: Qureshi
authors: Yoichi
authors: Y
authors: Takami
authors: Nikunj
authors: N
authors: Sharma
authors: Jerry B
authors: JB
authors: Lingrel
authors: Mukesh K
authors: MK
authors: Jain
mesh_terms: D000818:Animals; D002460:Cell Line; D004731:Endotoxins / Q000633:toxicity*; D006094:Gram-Positive Bacteria; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004731:Endotoxins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors