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Loss of NR2F6 reduces tissue-resident macrophages and protects from Salmonella typhimurium infection

ABSTRACT: Nuclear receptors regulate key functions of mononuclear phagocytes and are critical components of the innate immune system, acting as regulators of organ health and disease. In healthy mice, NR2F6 deficiency alters tissue-resident macrophage populations in the liver, lung, and spleen. In response to Salmonella Typhimurium infection, mice deficient in the nuclear receptor NR2F6 exhibit improved clinical outcomes, characterized by reduced weight loss, bacterial loads in the spleen and liver, and decreased plasma pro-inflammatory cytokines. Despite unchanged basal iron metabolism in the spleen and liver, iron regulatory proteins and the IL-6-hepcidin axis are altered in Nr2f6-deficient mice during Salmonella infection, reducing hypoferremia. Transcriptomic analysis of splenic red pulp macrophages reveals significant alterations of phagocytosis-related genes, including upregulation of Sirpa. In vitro, phagocytosis of red blood cells, regulated by the inhibitory CD47-Sirp axis, and Salmonella Typhimurium phagocytosis is significantly impaired in Nr2f6-deficient splenic macrophages. Blocking Sirp in vitro restores the phagocytic activity of Nr2f6-deficient macrophages to wild-type levels. In vivo, Salmonella Typhimurium loads are partially increased post-infection in anti-Sirp treated Nr2f6-deficient mice. These findings uncover a previously unrecognized role of NR2F6 in host-pathogen interactions, positioning it as a potential therapeutic target for infectious diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE250198 | GEO | 2025/07/06

REPOSITORIES: GEO

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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of LPS-TLR4 signalling and one report (Wu et al 2016) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wildtype (WT) and siglec E deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR-4 signalling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing 3 different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and –G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec E dependent alteration in macrophage phenotype that could be relevant to functional responses in host defence. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow derived DCs (BMDC), splenic DCs and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E.coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signalling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

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Loss of NR2F6 reduces tissue-resident macrophages and protects from Salmonella typhimurium infection

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