Similar Datasets
Project description:TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4+ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt+IL-17lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system-infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid-infiltrating CD4+ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.
| S-EPMC8685675 | biostudies-literature
Project description:TNF plays a crucial role in inflammation by signaling via T cell TNFR2 [bulkRNA-seq]
| PRJNA777869 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-11-06 | GSE188162 | GEO
Project description:TNF plays a crucial role in inflammation by signaling via T cell TNFR2
| PRJNA777866 | ENA
Project description:Identification of differentially expressed genes between WT and Tnfr2-/- CD4+ T cells in Experimental autoimmune encephalomyelitis (EAE).
2021-11-06 | GSE188161 | GEO
Project description:TNF plays a crucial role in inflammation by signaling via T cell TNFR2 [scRNA-seq]
| PRJNA777868 | ENA
Project description:Objectives: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in rheumatoid arthritis (RA). The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. Methods: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. Results. TNFR2 expression was increased in RA when compared to OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared to OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1 were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. Conclusion: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.
2022-04-26 | GSE195557 | GEO
Project description:TNF is a pleiotropic cytokine that exerts immunomodulatory functions mostly mediated by its interaction with the receptor TNFR2, highly expressed by regulatory T cells. However, Tregs can also produce TNF, and the existence of an autocrine TNF-TNFR2 loop has been proposed. Here, we describe that, indeed, both human and mouse Tregs can produce TNF in physiological conditions, in several mouse organs, and in mouse models of chronic inflammation and cancer. However, TNF production and TNFR2 expression are mutually exclusive in Tregs: indeed, TNFR2+ and TNFR2- Treg subsets are respectively poor and strong TNF producers. In TNFR2+ cells, TNF is both transcriptionally and post-transcriptionally controlled, through the repressing activity of microRNA-146a. The two subsets of TNFR2+ and TNFR2- Tregs partially maintain their different ability to produce TNF, when separately stimulated ex vivo. However, when cocultured, the TNFR2+ cells greatly outnumber the TNFR2- counterpart, and induce in TNFR2- cells the upregulation of Foxp3 and TNFR2, an event that is associated with the transfer of cytoplasmic material from TNFR2+ to TNFR2- cells. Functionally, TNFR2+ Tregs are endowed with superior suppressive activity, in association with a better survival in vitro. This phenotype could be attributed to an improved resistance to oxidative stress, as revealed by gene expression analysis and intracellular ROS staining. Overall, our data indicate that Tregs exist in two states, respectively committed to TNF production or TNF sensing through TNFR2, which cooperate in promoting the suppressive function of the whole Treg pool.
2025-09-23 | GSE291595 | GEO
Project description:Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin – a crucial MAS component – we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.
2025-09-30 | GSE309252 | GEO
Project description:Apo-A4 expression was increased in tissues from chronic kidney disease (CKD) patients compared to that in normal kidney tissue. We determined the association of apo-A4 and its regulatory signals following acute kidney injury and elucidated the effects of apo-A4 on cell signaling pathways related to kidney injury in vitro and in vivo. Tumor necrosis factor (TNF)-α, which causes inflammatory cell injury, induced significantly increased expression of apo-A4 protein levels, and these levels were related to pro-inflammatory acute kidney injury in human kidney cells. Apo-A4 expression was also increased in experimented rat kidney tissues after ischemic reperfusion injury. The expression of tumor necrosis factor receptor (TNFR) 2 was increased in both kidney cell lines and experimented rat kidney tissues following acute kidney injury. The expression of apo-A4 and TNFR2 was increased upon treatment with TNF-α. Immunohistochemistry revealed positive apo-A4 and TNFR2 staining in ischemic reperfusion injury rat kidneys compared with levels in the sham operation kidneys. After neutralization of TNF-α, NF-κB expression was only observed in the cytoplasm by immunofluorescence. Therefore, the apo-A4 expression is increased by stimulation of injured kidney cells with TNF-α and that these effects occur via a TNFR2-NFκB complex.
| S-EPMC5562825 | biostudies-literature