Innate triggering and antiviral effector functions of activin A
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190277 | GEO | 2021/12/08
REPOSITORIES: GEO
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Project description:Compares activin deficient granulosa cells (Inhba flox/-; Inhbb-/-; Amhr2cre/+) to wild type granulosa cells Keywords: Genetic Modificaton
2007-12-28 | GSE7150 | GEO
Project description:Compares activin deficient granulosa cells (Inhba flox/-; Inhbb-/-; Amhr2cre/+) to wild type granulosa cells Experiment Overall Design: Three replicate wild type granulosa cell samples compared to 2 activin-deficient granulosa cell samples. Each replicate is derived from 2-3 females.
2008-06-15 | E-GEOD-7150 | biostudies-arrayexpress
Project description:Heterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes Fibrodysplasia Ossificans Progressiva (FOP). We and others showed that activin A promotes both acquired and genetic HO and found that the retinoid agonist Palovarotene inhibits both HO forms in mice. We asked whether Palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq datasets indicated that the drug had reduced interactions and crosstalk amongst cell populations. Our data reveal that Palovarotene markedly reduces the number of local Inhba-expressing HO-forming populations.
2023-07-01 | GSE233843 | GEO
Project description:The important role of IGF-1R in cancers has been well established. Classical model involves IGF-1/2 binding to IGF-1R, following activation of the PI3K/Akt pathway, thereby promoting cell proliferation, apoptosis inhibition and treatment resistance. While IGF-1R has become a promising target for cancer therapy, clinical disclosures subsequently have been less encouraging. The question is whether targeting IGF/IGF-1R still holds therapeutic potential. Here we show a novel mechanism that knockdown IGF-1R surprisingly triggers cytoplasmic viral RNA sensors MDA5 and RIG-1, leading to mitochondrial apoptosis in cancer. We analyzed MDA5 and RIG-1 in the intestinal epithelium of IGF-1R knockdown mice. Igf1r+/- mice demonstrated higher MDA5 and RIG-1 than WT mice. IGF-1R knockdown-triggered MDA5 and RIG-1 was further analyzed in human cancer and normal cells. Increased MDA5 and RIG-1 were clearly seen in the cytoplasm identified by immunofluoresce in the cells silenced IGF-1R. Block off IGF-1R downstream PI3K/Akt did not impact on MDA5 and RIG-1 expression. IGF-1R knockdown-triggered MDA5 and RIG-1 and their signaling pathways were similar to those of viral RNA mimetic poly(I:C) had. IGF-1R knockdown-triggered MDA5 and RIG-1 led to cancer apoptosis through activation of the mitochondrial pathway. In vivo assay, Igf1r+/- mice strongly resisted AOM-induced colonic tumorigenesis through triggering MDA¬5- and RIG-1-mediated apoptosis. Notably, RIG-I and MDA5-mediated proapoptotic signaling pathway is preferential active in cancer cells. These data suggest that targeting IGF-1R-triggered MDA5 and RIG-1 might have therapeutic potential for cancer treatment.
2019-11-30 | GSE122534 | GEO
Project description:Heterotopic ossification (HO) consists of endochondral bone forming at extraskeletal anatomical sites. One form of HO is acquired and instigated by traumas or invasive surgery, and another form is genetic and severe and characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Previously, we showed that the synthetic retinoid agonist Palovarotene inhibits both acquired and genetic HO, and we and others subsequently showed that systemic administration of a neutralizing activin A antibody reduces both HO forms as well. Here, we asked whether Palovarotene’s action includes an interference with endogenous activin A expression and/or participation in HO. Using a standard mouse model of acquired HO, we found that activin A protein and encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in control untreated mice. Single cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in control HO, in addition to its expected expression in inflammatory cells and macrophages particularly. Palovarotene administration (4 mg/kg/day/gavage) caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq datasets indicated that the drug had reduced interactions and crosstalk amongst local cell populations. To determine if Palovarotene inhibited Inhba expression directly, we tested it in primary cultures of growth plate chondrocytes. Drug treatment inhibited cartilage phenotypic expression but not Inhba expression. Our data reveal that Palovarotene intersects with activin A during its anti-HO action and markedly reduces the number of local participating Inhba-expressing cell populations. The data broaden the spectrum of HO culprits against which Palovarotene acts, accounting for its therapeutic effectiveness.
2024-06-01 | GSE227253 | GEO
Project description:Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFβ in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA), which is typically associated with poor survival and advanced stage in ovarian cancer. Here, we identified INHBA(+) CAFs as key players in tumor promotion and immune evasion. In syngeneic ovarian cancer mouse models, intraperitoneal injection of the Activin A neutralizing antibody attenuated tumor progression and infiltration with the host INHBA(+) CAFs and M2 macrophages. Collectively, our study identified an INHBA(+) subset of pro-tumoral CAFs as a potential therapeutic target in ovarian cancer.
2023-05-01 | GSE229529 | GEO
Project description:Bone fraction healing is effective in most individuals, but can be subpar and not easily treatable in patients such as the elderly, requiring new remedies. Here we tested whether activin A promotes fracture repair, inspired by recent studies showing that the protein stimulates ectopic bone formation in other systems. Using a standard mouse tibia fracture model, we found that activin A became very abundant in the developing callus soon after fracture. Single cell RNA-seq and immunostaining showed that initially, expression of the activin A-encoding gene Inhba characterized inflammatory cells and periosteal mesenchymal lineage cells. Over time, Inhba expression became prominent in a unique, highly-proliferative progenitor cell (PPC) population that displayed a myofibroblast character and was at the center of a developmental trajectory bifurcation toward cartilage and bone cells in callus. Systemic administration of a neutralizing activin A monoclonal antibody delayed fracture healing, whereas local implantation of recombinant activin A enhanced it. Cells engaged in healing produced phosphorylated SMAD2 through which activin A normally signals intracellularly, and were also positive for aSMA, a recognized marker of myofibroblasts. In vitro gain- and loss-of-function assays showed that activin A directly stimulated chondrogenesis, osteogenesis and myofibroblast differentiation in periosteal progenitors. Our study reveals that activin A is a positive regulator of fracture repair and may represent a new therapeutic tool to enhance it. Its action involves a prominent and transient PPC population with a myofibroblastic character that would rapidly gear up to bring about repair in a timely and effective manner.
2024-01-11 | GSE192630 | GEO
Project description:The RIG-I-like receptors (RLRs: RIG-I, MDA5 and LGP2) trigger inflammatory and antiviral responses by sensing non-self RNA molecules produced during viral replication. LGP2 regulation of RIG-I and MDA5-dependant type-I interferon signaling is a matter of controversy. Here we show that LGP2 interacts with different components of the RNA silencing machinery. Particularly, we identified a direct protein-protein interaction between LGP2 and interferon-inducible double-stranded RNA-dependent protein kinase activator A (PACT). The LGP2-PACT interaction is mediated by the regulatory C-terminal domain of LGP2 and is necessary for inhibiting the RIG-I- and amplifying the MDA5-responses. We describe a point mutation within LGP2 that disrupts LGP2-PACT interaction and leads to the loss of LGP2 regulatory activity over RIG-I and MDA5. These results provide a model in which PACT-LGP2 interaction regulates RIG-I and MDA5 inflammatory response and allows cellular RNA silencing machinery to coordinate the innate immune response.
2019-10-02 | PXD013191 | Pride
Project description:We screened nine genetically diverse inbred mouse strains for differences in axonal growth of adult dorsal root ganglion (DRG) neurons on CNS myelin. Naïve DRG neurite outgrowth on myelin was very limited, but preconditioning the neurons by a prior sciatic nerve crush increased axonal growth substantially across all strains, with by far the greatest change in neurons from CAST/Ei mice. Three independent in vivo CNS injury models revealed greater capacity for CNS axonal regeneration in CAST/Ei than C57BL/6 mice. Full-genome expression profiling of naïve and pre-conditioned DRGs across all strains revealed Activin-βA (Inhba) as the transcript whose expression most closely correlated with axonal growth on myelin. In vitro and in vivo gain- and loss-of-function experiments confirmed that Activin promotes axonal growth in the CNS. Substantial regeneration is possible, therefore, in the injured mammalian CNS when Activin signaling is intrinsically high, as in CAST/Ei or when extrinsically modulated in other strains. 9 strains, 4 replicates per strain, 2 conditions (naïve and axotomy) = 72 samples. 2 samples were excluded because technical outliers (AJ_AX5D_1 and AJ_NAIVE_4 excluded from the normalized data but included in the raw data)
2015-05-14 | E-GEOD-55424 | biostudies-arrayexpress
Project description:Abstract Introduction Several environmental stimuli may influence lupus, especially viral infection. We utilize an imiquimod-induced lupus mouse model focusing on TLR7 pathway and use proteomics analysis to figure out the specific pathway related to viral infection and its related protein expressions in splenic B cells, hoping to get an insight on B cell responses to viral infection in lupus model. Material and methods. FVB/N wild type mouse was used treated with imiquimod for 8 weeks to induce lupus symptoms and signs, and splenocytes were retrieved, and B cells were selected and conducted proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another one week before Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and protein-protein interactome analyzed by STRING database in this lupus murine model. Results. The lupus model is well established and well demonstrated with serology evidence and pathology proof of lupus-mimic organ damage. Proteomics data of splenic B cells revealed the most important pathways activated (fold enrichment >100) were positive regulation of MDA-5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production and positive regulation of RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 have been demonstrated to be downstream effectors of MDA5 signaling. Finally, B cells intracellular cytosolic proteins were determined with Western blot experiment and the MDA5-related pathway activation is still evident. Conclusion. In this experiment, we confirmed that the B cells in lupus murine model focusing on TLR7 pathway were activated through MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmune. The MDA5 agonists/antagonist RNAs and detailed molecular interactions inside B cells are worthy further investigation for lupus therapy.
2023-03-10 | PXD034855 | Pride