Effective control of neuropathic pain by interrupting C/EBPβ-CLEC7A cross-talk-mediated NLRP3 inflammasome-dependent pyroptosis
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ABSTRACT:
PROVIDER: PRJNA768441 | ENA |
REPOSITORIES: ENA
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Project description:Neuropathic pain (NP) is a complex chronic pain due to the nervous system damage or diseases.During NP development and progression, the neuroinflammation has been observed along the pain pathways from the spinal cord to the thalamus and the parietal cortex. It may be caused by the activation of glial cells, especially microglia, with production of cytokines and other inflammatory mediators within the central nervous system (CNS), especially in spinal cord. In this study, we used high-throughput RNA-seq technology to detect the global gene expression in spinal cord of rats in sham group and CCI model group(an animal model of neuropathic pain), and the differentially expressed genes between diseases and control group were obtained.Significant differentially expressed genes (DEGs) of the Sham vs. CCI groups were identified using the criteria of a fold change>1.5 and P value <0.05. Finally, we focused on C/EBPβ-Clec7a Cross-talk-mediated NLRP3 Inflammasome-dependent Pyroptosis pathway and further studied its role in neuropathic pain.
2021-10-28 | GSE186237 | GEO
Project description:Therapeutic Interrupting C/EBPβ-Clec7a Cross-talk-mediated NLRP3 Inflammasome-dependent Pyroptosis for Relieving Neuropathic Pain
| PRJNA773054 | ENA
Project description:Neuropathic pain (NP) is a complex chronic pain due to the nervous system damage or diseases.During NP development and progression, the neuroinflammation has been observed along the pain pathways from the spinal cord to the thalamus and the parietal cortex. It may be caused by the activation of glial cells, especially microglia, with production of cytokines and other inflammatory mediators within the central nervous system (CNS), especially in spinal cord. In this study, we used microarrays to detect the global gene expression in spinal cord of rats in sham group and CCI model group(an animal model of neuropathic pain), and the differentially expressed genes between diseases and control group were obtained.
2021-10-05 | GSE185278 | GEO
Project description:BackgroundGrowing evidence shows that C-Type Lectin Domain Containing 7A (Clec7a) may be involved into neuroinflammatory injury of various neurological diseases. However, its roles in neuropathic pain remain unclear.MethodsA chronic constriction injury (CCI) rat model was constructed, and gene expression profilings in spinal cord tissues of CCI-insulted rats were detected by both microarray and RNA-seq studies. A series of bioinformatics analyses identified C/EBPβ-Clec7a to be a candidate axis involved into neuropathic pain. Then, its roles in mechanical allodynia, and pathological and molecular changes during CCI progression were determined by various gain-of-function and loss-of-function experiments in vivo and in vitro.ResultsSignificant upregulation of Clec7a at both mRNA and protein levels were verified in spinal cord tissues of CCI-insulted rats. Clec7a knockdown markedly attenuated CCI-induced mechanical allodynia, obstructed Syk, ERK and JNK phosphorylation, inhibited NLRP3 inflammasome and caspase-1 activation, GSDMD cleavage, and consequently reduced the release of pro-inflammatory cytokines (all P < 0.05). Mechanically, the rat Clec7a promoter was predicted to bind with transcription factor C/EBPβ, confirmed by Luciferase assay and ChIP-qPCR. Both in vivo and in vitro assays demonstrated that C/EBPβ knockdown significantly suppressed CCI- or LPS/ATP-induced Clec7a upregulation, and subsequently reduced Syk, ERK and JNK phosphorylation, NLRP3 oligomerization, caspase-1 activation, GSDMD expression and pyroptosis, which were markedly reversed by the co-transfection of Clec7a expression vector.ConclusionsThis pre-clinical investigation reveals that C/EBPβ-Clec7a axis may be a potential target for relieving neuropathic pain through alleviating neuroinflammation, paving its way for clinical translation as a promising approach for neuropathic pain therapy.
| S-EPMC9743596 | biostudies-literature
Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.
2023-09-18 | GSE217363 | GEO
Project description:Unexpected cross-talk between the pathogen defense mechanisms of apoptosis, necroptosis, and pyroptosis.
| PRJNA545997 | ENA
Project description:To characterize genome-wide C/EBPβ traget genes in C/EBPβ-overexpressed HL-60 cells by ChIP-seq.
2018-06-13 | GSE100486 | GEO
Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.
2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress
Project description:CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage but the involvement of the various C/EBPβ expressing cell types in this neuroprotective effect is not solved. Since C/EBPβ-deficient microglia show attenuated neurotoxicity in culture we hypothesized that specific C/EBPβ deficiency in microglia could be neuroprotective in vivo. In this study we have tested this hypothesis by generating mice with myeloid C/EBPβ deficiency. Mice with myeloid C/EBPβ deficiency were generated by crossing LysMCre and C/EBPβfl/fl mice . Primary microglial cultures from C/EBPβfl/fl (named here as WT) and LysMCre-C/EBPβfl/fl (named here as KO) mice were treated with lipopolysaccharide ± interferon γ (IFNγ) for 6 h and gene expression was analyzed by RNA sequencing. LysMCre-C/EBPβfl/fl mice showed an efficiency of C/EBPβ deletion of 100% in cultured microglia. Transcriptomic analysis of C/EBPβ-deficient primary microglia revealed C/EBPβ-dependent expression of 1068 genes, significantly enriched in inflammatory and innate immune responses GO terms. This study provides new data that support a central role for C/EBPβ in the biology of activated microglia.
2017-06-13 | GSE90046 | GEO
Project description:Malignant tumors display profound changes in cellular metabolism, yet how these altered metabolites affect the development and growth of tumors is not fully understood. Here, we used metabolomics to analyze the metabolic profile differences in ovarian cancer, and found that citric acid (CA) is the most significantly downregulated metabolite. Recently, CA has been reported to inhibit the growth of a variety of tumor cells, but whether it is involved in pyroptosis of ovarian cancer and its potential molecular mechanisms still remains to be further investigated. Here, we demonstrated that CA inhibits the growth of ovarian cancer cells in a dose-dependent manner. RNA-seq analysis revealed that CA significantly promoted the expression of thioredoxin interacting protein (TXNIP) and caspase-4 (CASP4). Morphologic examination by transmission electron microscopy indicated that CA-treated ovarian cancer cells exhibited typical pyroptosis characteristics. Further mechanistic analyses showed that CA facilitates pyroptosis via CASP4/TXNIP-NLRP3-Gesdermin-d (GSDMD) pathway in ovarian cancer. This study elucidated that CA induces ovarian cancer cell death through classical and non-classical pyroptosis pathways, which may be beneficial as an ovarian cancer therapy.
2022-08-01 | GSE189851 | GEO