TNFR1 signaling in sympathetic nerves dampens the inflammatory response in the bone marrow
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305591 | GEO | 2025/08/31
REPOSITORIES: GEO
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Project description:Athough anti-TNF therapies can be used to treat colitis associated with inflammatory bowel disease, in mice the loss of the TNF receptor TNFR1 (Tnfrsf1a) in the Il10-/- spontaneous colitis background results in acceleration of disease onset. Whereas Il10-/- mice on the Bl/6 background are relatively protected from colitis throughout life, Il10-/- Tnfr1-/- mice develop colitis beginning at 4 wks of age. Their disease results in nearly 50% mortality by 12 wks of age. Strikingly, Tnfr1-/- mice (with functional IL-10) exhibit evidence of mucosal dysfunction at 4 and 12 wks of age. These mucosal abnormalities include loss of barrier integrity, increased epithelial cell proliferation, crypt malformations, and increased immune cell infiltrate. Because of the early onset of mucosal abnormalities in Tnfr1-/- mice, with or without IL-10 expression, we hypothesized that TNFR1 plays important roles in colonic mucosal function in early life, prior to weaning. To test this hypothesis, we profiled, using mRNA-Seq, the colonic transcriptomes from wildtype and Tnfr1-/- mice at 2 wks of age. The results demonstrate that Tnfr1-/- mice have important gene expression changes, including reduced expression of Il1b, a marker of the proinflammatory "weaning reaction" that is required for establishment of mucosal tolerance in later life. TNFR1 therefore has key roles in colonic mucosal homeostasis in early life.
2020-08-05 | GSE155654 | GEO
Project description:We have compared mRNA expression in full-thickness mouse colon between wildtype mice and mice with a genetic deletion in tumor necrosis factor receptor 1 (TNFR1, encoded by the Tnfrsf1a gene). This experiment was motivated by our observation that Il10-/- Tnfr1-/- double-knockout mice develop very-early-onset colitis at the time of weaning, significantly earlier than disease onset in Il10-/- single-knockout mice. This suggests that TNFR1 mediates protection from colitis. To understand these protective mechanisms at the transcript level in a non-inflammatory context, we performed transcriptome profiling (mRNA-Seq) on colons from 12-week-old Tnfr1-/- mice, which do not develop colitis, and wildtype littermates. These experiments revealed that an estimated 510 transcripts were upregulated and 377 downregulated in colonic tissue of Tnfr1-/- mice. We aggregated the transcript information to calculate gene expression and performed gene set enrichment analysis to identify signaling pathways altered in Tnfr1-/- mice. When queried against a high-confidence set of 50 signaling pathways, the Tnfr1-/- gene expression profile was associated with reduced mitosis and increased glycolysis, transforming growth factor beta signaling, DNA repair, and reactive oxygen species signaling. Gene ontological analysis classified some of the differentially expressed genes into cytokines, junctional proteins, and transcription factors, but within these groups there was no consensus on the direction of regulation. We also examined how differentially expressed transcripts (called the TNFR1-regulated transcriptome) compared to differentially expressed colonic transcripts from previously collected Tnfr2-/- animals (or the TNFR2-regulated transcriptome, available at the NCBI Gene Expression Omnibus under the accession GSE65408). The raw data were re-analyzed with the current pipeline to enable comparison. There was almost no correlation between TNFR1- and TNFR2-regulated transcripts. Only 30 (~3%) TNFR1-regulated transcripts were also TNFR2-regulated transcripts, and ~4% of the TNFR2-regulated genes were also TNFR1-regulated genes. Of the few co-regulated transcripts, there was a significant negative correlation in their direction of regulation in Tnfr1-/- versus Tnfr2-/- colons. Collectively these results indicate that TNFR1 and TNFR2 have mostly different and opposing effects on gene expression in the mouse colon. MANUSCRIPT ABSTRACT: BACKGROUND & AIMS: Very-early-onset inflammatory bowel disease (VEO-IBD) is a devastating disease beginning in early childhood, refractory to anti-tumor necrosis factor (anti-TNF) therapies, and associated with mutations in the interleukin 10 (IL-10) pathway. Contrary to mainstream clinical practice, cellular and animal studies have shown beneficial roles of TNF signaling in colitis, but how these roles are encoded through TNF’s receptors remains unknown. Here we examined the role of TNF receptor 1 (TNFR1, or p55) in modulating the onset and severity of colitis in the interleukin 10 (IL-10)-deficient mouse model. METHODS: Colitis severity was compared between Il10-/- Tnfr1-/- and Il10-/-- littermate mice at 2-12 weeks of age. To assess dysbiosis as a potential pathogenic mechanism, Il10-/- Tnfr1-/- mice were treated with neomycin and metronidazole and their cecal contents analyzed by 16S rRNA sequencing. Gene expression, barrier function, and epithelial proliferation and apoptosis were examined in adult colitis-free Tnfr1-/- wildtype littermates. RESULTS: In contrast to relatively healthy Il10-/- mice, Il10-/- Tnfr1-/- mice developed severe, antibiotic-treatable colitis shortly after weaning. Microbiotal composition was similar between Il10‑/- Tnfr1-/- mice and Il10-/- littermate controls. Tnfr1-/- mice expressed transcripts associated with reactive oxygen species and DNA repair pathways. Tnfr1-/- mice exhibited focal areas of crypt branching, higher colonic epithelial permeability, and hallmarks of DNA damage. CONCLUSIONS: TNFR1 promotes epithelial homeostasis and regulates commensal exposure. The lack of TNFR1 accelerates the onset and severity of IBD in the absence of tolerogenic signaling (i.e., lack of IL-10). Il10-/- Tnfr1-/- mice may serve as a valuable model of very-early-onset IBD (VEO-IBD).
2019-03-15 | GSE107933 | GEO
Project description:Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin à receptor (LTÃR). Circumstantial evidence has linked the SMC LTÃR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTÃR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-κB pathway, whereas LTÃR signaling by agonistic anti LTÃR antibody activated both the classical RelA and alternative RelB NF-κB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTÃR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTÃR-RelB activation component of NF-κB signaling was obligatory to generate the LTO phenotype. TNFR1-LTÃR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTÃR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy. Experiment Overall Design: Smooth muscle cells in tissue culture were stimulated with agonists and subsequently microarray, RT-PCR, and protein assays / analyses were performed
2009-12-02 | E-GEOD-15062 | biostudies-arrayexpress
Project description:Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin ß receptor (LTßR). Circumstantial evidence has linked the SMC LTßR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTßR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-κB pathway, whereas LTßR signaling by agonistic anti LTßR antibody activated both the classical RelA and alternative RelB NF-κB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTßR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTßR-RelB activation component of NF-κB signaling was obligatory to generate the LTO phenotype. TNFR1-LTßR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTßR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy.
2009-11-23 | GSE15062 | GEO
Project description:Most MS-based approaches to study protein-protein interactions require homogenization of the cells, which leads to loss of the cellular structures, dilution of proteins and formation of incorrect protein complexes. Furthermore, several purification and washing steps are needed, which can lead to the loss of (weaker) interactions. We recently developed a new method for studying protein complexes without interfering with the cellular integrity; Virotrap. By trapping and purifying protein complexes in virus-like particles, we avoid cell lysis and preserve intact complexes during the purification process. Here, we present a protein-protein interaction network of the TNFR1-induced NF-κB and apoptosis pathway, using TRADD, FADD, TRAF2, cIAP1, NEMO, TANK, HOIL1, HOIP, SHARPIN, A20, ABIN1 and ABIN2 as baits in Virotrap. Virotrap was applied both under resting conditions as well as upon TNF stimulation, which reveals dynamic interactions in TNFR1-induced NF-κB signaling. The found interactions compromise both known interactors as well as novel ones that might serve as valuable resource for further unraveling the molecular mechanisms controlling inflammation, cellular proliferation and cell death.
2018-11-06 | PXD009366 | Pride
Project description:Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4 binding protein 1 (N4BP1) was recently identified as a critical suppressor of proinflammatory cytokine production1, whose mode of action remained unknown. Here, we show that N4BP1 is a novel linear ubiquitin receptor that negatively regulates NFB signalling by its unique dimerization-dependent ubiquitin-binding module. N4BP1 homo-oligomerization strategically positions two non-selective ubiquitin-binding domains, ensuring exclusive recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex where it, through linear ubiquitin binding, regulates stability of the TNFR1 signalling complex and duration of proinflammatory signalling. N4BP1 deficiency accelerates TNF-induced cell death by increasing complex II assembly. Under proapoptotic conditions, Caspase-8 mediates proteolytic processing of N4BP1 and the resulting cleavage fragment of N4BP1, which retains the ability to bind linear ubiquitin, is rapidly degraded by the 26S proteasome, accelerating apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a unique linear ubiquitin reader that ensures timely and coordinated regulation of TNFR1-mediated inflammation and cell death.
2024-05-22 | PXD024355 | Pride
Project description:The loss of TNFR1 (Tnfrsf1a) in the Il10-/- spontaneous mouse colitis background results in acceleration of disease onset. Whereas Il10-/- mice on the Bl/6 background are relatively protected from colitis throughout life, Il10-/- Tnfr1-/- mice develop colitis beginning at 4 wks of age. Their disease results in nearly 50% mortality by 12 wks of age. We hypothesized that this early-onset colitis was due to dysregulation of immune signals in early life, defining a key period known as the "weaning reaction" in which proinflammatory signals help induce mucosal tolerance of the microbiome. To test this hypothesis, we profiled, using mRNA-Seq, the colonic transcriptomes from Il10-/- and Il10-/- Tnfr1-/- mice at 2 wks of age. The results presented here show that Il10-/- Tnfr1-/- mice have reduced expression of cytokines at this early age, suggesting that they cannot amount an appropriate immune response. Thus, TNFR1 plays an important role in the weaning reaction and the acquisition of tolerance.
2020-08-04 | GSE155626 | GEO
Project description:Human colon carcinoma cells SKCO1 were deprived of either beta-catenin alone or beta-catenin together with TNFR1 and changes in mRNA levels were examined before and after TNFR1 ablation SKCO1 cells were transfected with either beta-catenin-specific siRNA alone or beta-catenin-specific siRNA together with a TNFR1-specific siRNA and changes in mRNA levels were examined before and after TNFR1 ablation
2014-10-02 | E-GEOD-61961 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSCs) inhabit distinct microenvironments within the adult bone marrow (BM) that govern the delicate balance between HSC quiescence, self-renewal, and differentiation. It has been suggested that quiescent HSCs localize adjacent to BM arteriole endothelial cells in a significant and non-random distribution. This data suggests that the arteriole BM vascular niche may be the primary HSC niche. Because the BM arteriole niche is composed of tightly-associated pericytes, including smooth muscle actin+, LepR+, Nestin+, NG2+, and nonmyelinating Schwann cells, we sought to begin to uncouple the arteriole BM EC niche by examining its capacity to support the maintenance and expansion of HSCs ex vivo and in vivo. We developed a method to isolate and culture BM arteriole endothelial cells in serum-/growth factor-free conditions, allowing for a non-biased approach to examining their instructive function. Utilizing our protocol, we demonstrate that BM endothelial cells, but not BM stromal cells, have the capacity to expand long-term repopulating, multi-lineage HSCs in lieu of complex serum and cytokine supplementation. In addition, transplantation of arteriole endothelial cells promoted rapid hematopoietic recovery and protected HSCs following an LD50 dose of myeloablative irradiation. These data demonstrate that arteriole-derived BM endothelial cells are endowed with the necessary signals to support the self-renewal and regenerative capacity of LT-HSCs and that transplantation of arteriole BM endothelial cells could be used as a therapeutic means to decrease pancytopenias associated with myeloablative treatments to treat a wide array of disease states.
2015-11-04 | GSE61636 | GEO
Project description:Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-ĸB essential modulator in hepatocytes (NemoΔhepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoΔhepa mice. Therefore, we generated NemoΔhepa/TRAIL-/- and NemoΔhepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoΔhepa/TRAIL-/- displayed a similar phenotype to NemoΔhepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoΔhepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoΔhepa and NemoΔhepa/TRAIL-/- mice while NemoΔhepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoΔhepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice. Expression profiling of livers from wild type, NEMO, NEMO-TRIAL, and NEMO-TNFR null mice
2014-09-03 | E-GEOD-33161 | biostudies-arrayexpress