EDA2R signaling drives cancer-associated skeletal muscle wasting [bulkRNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE245799 | GEO | 2024/07/13
REPOSITORIES: GEO
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Project description:We report that increased mRNA-expression of Ectodysplasin-A2-Receptor (EDA2R) is the most remarkable aging-associated transcriptional perturbation in humans and that its induction is confirmed in murine-models of Hutchinson-Gilford progeria syndrome and in other species. Up-regulation of EDA2R occurs in all solid-tissues and is complemented by the progressive transcriptional increase of its ligand in bloodstream. Strengthening of EDA2R/EDA-A2 signaling may exacerbate inflammation in ageing individuals which might be prevented by EDA2R/EDA-A2 blockade.
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Project description:We report that increased mRNA-expression of Ectodysplasin-A2-Receptor (EDA2R) is the most remarkable aging-associated transcriptional perturbation in humans and that its induction is confirmed in murine-models of Hutchinson-Gilford progeria syndrome and in other species. Up-regulation of EDA2R occurs in all solid-tissues and is complemented by the progressive transcriptional increase of its ligand in bloodstream. Strengthening of EDA2R/EDA-A2 signaling may exacerbate inflammation in ageing individuals which might be prevented by EDA2R/EDA-A2 blockade.
2024-09-13 | E-MTAB-14234 | biostudies-arrayexpress
Project description:We report that increased mRNA-expression of Ectodysplasin-A2-Receptor (EDA2R) is the most remarkable aging-associated transcriptional perturbation in humans and that its induction is confirmed in murine-models of Hutchinson-Gilford progeria syndrome and in other species. Up-regulation of EDA2R occurs in all solid-tissues and is complemented by the progressive transcriptional increase of its ligand in bloodstream. Strengthening of EDA2R/EDA-A2 signaling may exacerbate inflammation in ageing individuals which might be prevented by EDA2R/EDA-A2 blockade.
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Project description:EDA2R signaling drives cancer-associated skeletal muscle wasting [bulkRNA-Seq]
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Project description:Investigating muscle wasting in a murine model of cancer cachexia, we identified Oncostatin M (OSM) as a potential mediator of inflammatory responses in skeletal muscle. OSM is a member of the IL-6 family of cytokines and has crucial functions in cell growth, differentiation, and inflammation. Our results demonstrate that OSM induces muscle atrophy. To understand if its effect is specific or it is a general effect of IL6 family cytokines, primary myotubes were treated with OSM, IL6 and LIF for 48hrs. Our findings showed that OSM potently induces muscle wasting in differentiated myotubes.
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Project description:The microenvironment of injured mucosa has important effects on intestinal stem cell self-renewal and reconstruction of epithelial barrier function in inflammatory bowel disease (IBD). However, the precise status of the interactions between intestinal epithelial cell (IEC) injury, particularly intestinal crypt absence, and microenvironment in IBD is not completely understood. We identified miR-494-3p as important for protection of colonic stemness in intestinal inflammation colonic organoid culture. A novel cytokine-cytokine receptor, EDA-A2/EDA2R, could suppress colonic stemness and epithelial repair during IBD. During intestinal inflammation, high level of LP macrophage-derived EDA-A2 inhibited the nuclear β-catenin/c-Myc axis and organoid growth by targeting EDA2R in colonic crypt stem cells. We further demonstrated that the pro-inflammatory cytokines IL-1β and IL-6 are capable of stimulating macrophages to release EDA-A2 during colitis. Secondly, we identified the cross-talk among IECs, colonic crypts, and lamina propria (LP) macrophages in miR-494-3p-mediated colitis. Furthermore, our study showed that miR-494-3p deficiency in IECs promoted LP macrophage recruitment and M1 activation in DSS-induced colitis mice. In addition, we identified miR-494-3p as critical to dampening IEC injury; specifically, miR-494-3p inhibited inflammation-induced IKKβ/NF-κB activation by targeting the IKKβ 3’UTR in IECs. As such, administration of adequate amounts of a miR-494-3p agomire attenuate colitis in vivo. Consistent with this inference, we showed that miR-494-3p levels were decreased in colonic crypts and serum in colitis mice, and loss of miR-494 potentiated the severity of colonic colitis. Our clinical data on the interactions between miR-494-3p levels in serum exosomes & colonic tissues and associated outcomes support the clinical relevance of miR-494-3p in IBD. The miR-494-3p agomir system, which we designed permits local delivery in vivo in this study, significantly ameliorated the severity of colonic colitis. Our findings no only uncover a miR-494-3p-mediated cross-talk mechanism by which inflamed colonic LP macrophages integrate signals from IECs to regulate colonic stemness and colonic epithelial repair/homeostasis. The miR-494-3p agomir may serve as a potential therapeutic approach in IBD.
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Project description:The microenvironment of injured mucosa has important effects on intestinal stem cell self-renewal and reconstruction of epithelial barrier function in inflammatory bowel disease (IBD). However, the precise status of the interactions between intestinal epithelial cell (IEC) injury, particularly intestinal crypt absence, and microenvironment in IBD is not completely understood. We identified miR-494-3p as important for protection of colonic stemness in intestinal inflammation colonic organoid culture. A novel cytokine-cytokine receptor, EDA-A2/EDA2R, could suppress colonic stemness and epithelial repair during IBD. During intestinal inflammation, high level of LP macrophage-derived EDA-A2 inhibited the nuclear β-catenin/c-Myc axis and organoid growth by targeting EDA2R in colonic crypt stem cells. We further demonstrated that the pro-inflammatory cytokines IL-1β and IL-6 are capable of stimulating macrophages to release EDA-A2 during colitis. Secondly, we identified the cross-talk among IECs, colonic crypts, and lamina propria (LP) macrophages in miR-494-3p-mediated colitis. Furthermore, our study showed that miR-494-3p deficiency in IECs promoted LP macrophage recruitment and M1 activation in DSS-induced colitis mice. In addition, we identified miR-494-3p as critical to dampening IEC injury; specifically, miR-494-3p inhibited inflammation-induced IKKβ/NF-κB activation by targeting the IKKβ 3’UTR in IECs. As such, administration of adequate amounts of a miR-494-3p agomire attenuate colitis in vivo. Consistent with this inference, we showed that miR-494-3p levels were decreased in colonic crypts and serum in colitis mice, and loss of miR-494 potentiated the severity of colonic colitis. Our clinical data on the interactions between miR-494-3p levels in serum exosomes & colonic tissues and associated outcomes support the clinical relevance of miR-494-3p in IBD. The miR-494-3p agomir system, which we designed permits local delivery in vivo in this study, significantly ameliorated the severity of colonic colitis. Our findings no only uncover a miR-494-3p-mediated cross-talk mechanism by which inflamed colonic LP macrophages integrate signals from IECs to regulate colonic stemness and colonic epithelial repair/homeostasis. The miR-494-3p agomir may serve as a potential therapeutic approach in IBD.
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