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A study of cecal ligation and puncture-induced sepsis in tissue-specific tumor necrosis factor receptor 1-deficient mice

Authors
  • Vandewalle, Jolien
  • Steeland, Sophie
  • Van Ryckeghem, Sara
  • Eggermont, Melanie
  • Van Wonterghem, Elien
  • Vandenbroucke, Roosmarijn
  • Libert, Claude
Publication Date
Jan 01, 2019
Identifiers
DOI: 10.3389/fimmu.2019.02574
OAI: oai:archive.ugent.be:8639699
Source
Ghent University Institutional Archive
Keywords
Language
English
License
Green
External links

Abstract

Sepsis is a complex syndrome resulting from a dysregulated immune response to an infection. Due to the high prevalence, morbidity, and mortality, there is a lot of interest in understanding pathways that play a role in sepsis, with a focus on the immune system. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine and a master regulator of the immune system but clinical trials with TNF blockers in sepsis have failed to demonstrate significant protection. Since TNF stimulates two different receptors, TNF receptor 1 (TNFR1) and TNFR2, pan-TNF inhibition might be suboptimal since both receptors have opposite functions in polymicrobial sepsis. Therefore, we hypothesized that TNF has a dual role in sepsis, namely a mediating and a protective role, and that protection might be obtained by TNFR1-specific inhibition. We here confirmed that TNFR1(-/-) mice are protected in the sterile endotoxemia model, whereas TNFR1 deficiency did not protect in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. Since whole body TNFR1 blockage might be deleterious because of the antibacterial function of TNF/TNFR1 signaling, we focused on the potential devastating role of TNF/TNFR1 signaling in specific cell types. We were interested in the gut epithelium, the endothelium, and hepatocytes using conditional TNFR1(-/-) mice, as these cell types have been shown to play a role in sepsis. However, none of these conditional knockout mice showed improved survival in the CLP model. We conclude that cell-specific targeting of TNFR1 to these cell types has no therapeutic future in septic peritonitis.

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