Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis

Abstract

c 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 wildtype 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 ␤-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.

DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C

“…Nevertheless, our data suggest that chronic overexpression (and thus, overactivation) of HOXD10, and also lack of HOXD10, do have a clear effect on LEC junctional integrity and permeability. In this context, it is interesting that NR4A1, the immediate early transcription factor dependent on HOXD10, has been found to regulate permeability in blood vascular endothelial cells, by reducing expression of VE-cadherin and claudin-5, and by inducing NOS3 (also known as e-NOS) (Hamers et al, 2014;Zhao et al, 2011). In line with those findings, we found similar changes in gene expression in LECs overexpressing HOXD10, suggesting that HOXD10 could regulate LECs permeability through NR4A1.…”

The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor

“…macrophage NF-kB signaling 65 . Other studies have indicated that Nr4a1 does not alter immune cell responses but instead antagonizes endothelial responses to inflammation 66 . In regards to the CNS, Nr4a1 has been implicated in adult brain injury to promote neuroinflammation and cell death 17,18 .…”

Targeting monocyte and macrophage subpopulations for immunotherapy: a patent review (2009 – 2013)

“…Unfortunately, subsequent research has failed to replicate these findings, either in bone--marrow-derived macrophages or in vivo [55]. In addition, Nr4a1 -/-mice have a normal immune response in a model of Escherichia coli peritonitis, with no difference in bacterial load, cytokine profile or leukocyte numbers [56]. NR4A1 does not solely exert its effects in myeloid cells, and there is little consideration in this patent or the literature of the consequences of its systemic activation or inhibition.…”