title: A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis.
abstract: Vascular injury is a serious complication of sepsis due to the gram-negative bacterium Neisseria meningitidis. One of the critical early steps in initiating this injury is via the interaction of leucocytes, particularly neutrophils, with adhesion molecules expressed on inflamed endothelium. We have previously demonstrated that both lipopolysaccharide (LPS) and non-LPS components of meningococci can induce very high levels of expression of the vascular endothelial cell adhesion molecule E-selectin, which is critical for early tethering and capture of neutrophils onto endothelium under flow. Using an LPS-deficient strain of meningococcus, we showed that very high levels of expression can be induced in primary endothelial cells, even in the context of weak activation of the major host signal transduction factor [nuclear factor-κB (NF-κB)]. In this study, we show that the particular propensity for N. meningitidis to induce high levels of expression is regulated at a transcriptional level, and demonstrate a significant role for phosphorylation of the ATF2 transcription factor, likely via mitogen-activated protein (MAP) kinases, on the activity of the E-selectin promoter. Furthermore, inhibition of E-selectin expression in response to the lpxA- strain by a p38 inhibitor indicates a significant role of a p38-dependent MAPK signalling pathway in ATF2 activation. Collectively, these data highlight the role that LPS and other bacterial components have in modulating endothelial function and their involvement in the pathogenesis of meningococcal sepsis. Better understanding of these multiple mechanisms induced by complex stimuli such as bacteria, and the specific inflammatory pathways they activate, may lead to improved, focused interventions in both meningococcal and potentially bacterial sepsis more generally.
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.|Department of Biology, Faculty of Science, University of Regina, Regina, SK, Canada.
authors.forename: M C
authors.identifier: http://orcid.org/0000-0003-2025-9901
authors.initials: MC
authors.lastname: Jacobsen
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.|Science for Life Laboratory, Clinical Applied Proteomics, School of Biotechnology, Royal Institute of Technology (KTH), Solna, Sweden.
authors.forename: P J
authors.initials: PJ
authors.lastname: Dusart
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Kotowicz
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bajaj-Elliott
authors.affiliation: Experimental and Personalised Medicine Section, Institute of Child Health, University College London, London, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Hart
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Klein
authors.affiliation: Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London, London, UK.|Department of Microbiology, Great Ormond Street Hospital, London, UK.
authors.forename: G L
authors.initials: GL
authors.lastname: Dixon
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism*; D042783:Endothelial Cells / Q000382:microbiology* / Q000502:physiology*; D004731:Endotoxins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009345:Neisseria meningitidis / Q000502:physiology*
chemical_list: D051698:Activating Transcription Factor 2; D019040:E-Selectin; D004731:Endotoxins