title: Limited role of nuclear receptor Nur77 in Escherichia coli-induced peritonitis.
abstract: Nuclear receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to play an anti-inflammatory role in macrophages, which have a crucial function in defense against peritonitis. The function of Nur77 in Escherichia coli-induced peritoneal sepsis has not yet been investigated. Wild-type and Nur77-knockout mice were inoculated with E. coli, and bacterial outgrowth, cell recruitment, cytokine profiles, and tissue damage were investigated. We found only a minor transient decrease in bacterial loads in lung and liver of Nur77-knockout compared to wild-type mice at 14 h postinfection, yet no changes were found in the peritoneal lavage fluid or blood. No differences in inflammatory cytokine levels or neutrophil/macrophage numbers were observed, and bacterial loads were equal in wild-type and Nur77-knockout mice at 20 h postinfection in all body compartments tested. Also, isolated peritoneal macrophages did not show any differences in cytokine expression patterns in response to E. coli. In endothelial cells, Nur77 strongly downregulated both protein and mRNA expression of claudin-5, VE-cadherin, occludin, ZO-1, and β-catenin, and accordingly, these genes were upregulated in lungs of Nur77-deficient mice. Functional permeability tests pointed toward a strong role for Nur77 in endothelial barrier function. Indeed, tissue damage in E. coli-induced peritonitis was notably modulated by Nur77; liver necrosis and plasma aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) levels were lower in Nur77-knockout mice. These data suggest that Nur77 does not play a role in the host response to E. coli in the peritoneal and blood compartments. However, Nur77 does modulate bacterial influx into the organs via increased vascular permeability, thereby aggravating distant organ damage.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
authors.forename: Sven
authors.initials: S
authors.lastname: Uleman
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Kruijswijk
authors.forename: Anne-Marieke
authors.initials: AM
authors.lastname: van Stalborch
authors.forename: Stephan
authors.initials: S
authors.lastname: Huveneers
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000382:microbiology; D008168:Lung / Q000166:cytology / Q000382:microbiology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000502:physiology*; D010518:Periodontitis / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D010529:Peritoneal Cavity / Q000382:microbiology
chemical_list: D016207:Cytokines; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1