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Project description:IFN-kappa Suppresses the Replication of Influenza A Virus through IFNAR-MAPK-Fos-CHD6 Axis
| PRJNA598132 | ENA
Project description:TPL-2 kinase plays an important role in innate immunity, activating ERK1/2 MAPKs in myeloid cells following TLR stimulation. We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos -/- macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.
| S-EPMC9012084 | biostudies-literature
Project description:Degenerative joint disease mainly manifests abnormal bone and cartilage remodeling, articular disc deformation and synovial inflammation, and it is closely related to intraarticular overload. Activation of the mechanosensitive channel transient receptor potential vanilloid 4 (TRPV4) can lead to degeneration of the temporomandibular joint (TMJ) disc. However, the potential mechanism by which TRPV4 leads to TMJ degeneration are still unclear. The results showed that TRPV4 activation promoted upregulation of chemokines including CXCL6 and CXCL13 in disc cells, and such chemokine release facilitated the proliferation and migration of FLSs and aggravated the TMJ degeneration in rat. Mechanistically, TRPV4-induced p38 MAPK signaling pathway activation promoted chemokine expression via the nuclear translocation of p38 and c-Fos, thereby promoting the proliferation and migration by CXCL-CXCR interaction.
2024-11-07 | GSE280821 | GEO
Project description:The phytochemical substances, coumarin derivatives, have demonstrated antiresorptive bone effects by suppressing osteoclast differentiation in vitro and in vivo. Recently, we have identified 5'-hydroxy auraptene (5'-HA), a coumarin derivative isolated from Lotus lalambensis Schweinf, as a novel stimulator for osteoblast differentiation. In this study, we investigated the effect of 5'-HA on osteoclast differentiation of mouse bone marrow (BM) cells. The effect of 5'-HA on BM cell proliferation and osteoclast differentiation was determined by measuring cell viability and tartrate-resistant acid phosphatase (TRAP) enzyme activity, quantification of TRAP+ multinucleated cells (TRAP+MNCs), and quantitative real-time PCR (qPCR) of osteoclastic gene expression. Regulation of NF-κB, c-Fos/NFATc1, and MAPK signaling pathways by 5'-HA during osteoclastogenesis was measured by the NF-κB reporter assay and Western blot analysis. 5'-HA significantly suppresses the receptor activator of NF-κB ligand (RANKL) induced osteoclast differentiation of BM cells in a dose-dependent manner. Consistently, treatment of BM cells with 5'-HA significantly inhibited RANKL-induced activation of NF-κB and c-Fos/NFATc1 pathways in a dose-dependent manner. Furthermore, RANKL-induced phosphorylation of ERK1/2, p-38, and JNK was significantly inhibited by 5'-HA in BM cells. In conclusion, we identified 5'-HA as a novel coumarin derivative that suppresses RANKL-induced osteoclastogenesis via inhibiting c-Fos/NFATc1 and MAPK signaling pathways.
| S-EPMC6949687 | biostudies-literature
Project description:Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack host cellular machinery for its replication. Host cells have evolved diverse cellular defense to resist the invasion of viruses. As the main components of promyelocytic leukemia protein nuclear bodies (PML-NBs), PML can inhibit the replication of many medically important viruses including IAV. However, the mechanism of PML against IAV is unclear. In the present study, we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication, whereas knockdown of endogenous PML expression could enhance IAV replication. Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2, which negatively regulated IAV replication during infection. Moreover, PML stabilized RIG-I to promote the production of type I IFN. Collectively, these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity.
| S-EPMC8645530 | biostudies-literature
Project description:Lactate, traditionally considered a metabolic by-product, has recently been identified as a substrate for the induction of lactylation, a newly identified epigenetic modification that plays an important role in the regulation of host gene expression. Our previous study showed that lactate levels were significantly elevated in cells infected with the porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide for over 30 years. However, the role of elevated lactate in PRRSV infections remains unknown. In this study, we found that lactate was required for optimal PRRSV proliferation, and PRRSV infection increased cellular lactylation in a dose-dependent manner. Using the Cleavage Under Targets and Tagmentation (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by negatively modulating interferon (IFN)-β induction. Mechanistically, HSPA6 impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), thereby hindering the production of IFN-β. Taken together, these results indicate that the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing IFN-β induction, providing new therapeutic targets for the prevention and control of PRRSV infection. The results presented here also link lactylation to the virus life cycle, improving our understanding of epigenetic regulation in viral infection.IMPORTANCEAs a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-β production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.
| S-EPMC10804950 | biostudies-literature
Project description:The miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. While in vitro evidence suggests a tumor suppressor role for miR-29 in melanoma, the mechanisms underlying its deregulation and contribution to melanomagenesis have remained elusive. Using various in vitro systems, we show that oncogenic MAPK signaling paradoxically stimulates transcription of pri-miR-29b1~a and pri-miR-29b2~c, the latter in a p53-dependent manner. Expression analyses in melanocytes, melanoma cells, nevi, and primary melanoma revealed that pri-miR-29b2~c levels decrease during melanoma progression. Inactivation of miR-29 in vivo with a miRNA sponge in a rapid melanoma mouse model resulted in accelerated tumor development and decreased overall survival, verifying tumor suppressive potential of miR-29 in melanoma. Through integrated RNA sequencing, target prediction, and functional assays, we identified the transcription factors MAFG and MYBL2 as bona fide miR-29 targets in melanoma. Our findings suggest that attenuation of miR-29b2~c expression promotes melanoma development, at least in part, by derepressing MAFG and MYBL2.
| S-EPMC8003541 | biostudies-literature
Project description:MicroRNAs have been shown to contribute to a repertoire of host-pathogen interactions during viral infection. Our previous study demonstrated that microRNA-30e* (miR-30e*) directly targeted the IκBα 3'-UTR and disrupted the NF-κB/IκBα negative feedback loop, leading to hyperactivation of NF-κB. This current study investigated the possible role of miR-30e* in the regulation of innate immunity associated with dengue virus (DENV) infection. We found that DENV infection could induce miR-30e* expression in DENV-permissive cells, and such an overexpression of miR-30e* upregulated IFN-β and the downstream IFN-stimulated genes (ISGs) such as OAS1, MxA and IFITM1, and suppressed DENV replication. Furthermore, suppression of IκBα mediates the enhancing effect of miR-30e* on IFN-β-induced antiviral response. Collectively, our findings suggest a modulatory role of miR-30e* in DENV induced IFN-β signaling via the NF-κB-dependent pathway. Further investigation is needed to evaluate whether miR-30e* has an anti-DENV effect in vivo.
| S-EPMC4133224 | biostudies-literature
Project description:Macrophages use an array of innate immune sensors to detect intracellular pathogens and to tailor effective antimicrobial responses. In addition, extrinsic activation with the cytokine IFN-γ is often required as well to tip the scales of the host-pathogen balance toward pathogen restriction. However, little is known about how host-pathogen sensing impacts the antimicrobial IFN-γ-activated state. It was observed that in the absence of IRF3, a key downstream component of pathogen sensing pathways, IFN-γ-primed macrophages more efficiently restricted the intracellular bacterium Legionella pneumophila and the intracellular protozoan parasite Trypanosoma cruzi. This effect did not require IFNAR, the receptor for Type I IFNs known to be induced by IRF3, nor the sensing adaptors MyD88/TRIF, MAVS, or STING. This effect also did not involve differential activation of STAT1, the major signaling protein downstream of both Type 1 and Type 2 IFN receptors. IRF3-deficient macrophages displayed a significantly altered IFN-γ-induced gene expression program, with up-regulation of microbial restriction factors such as Nos2. Finally, we found that IFN-γ-primed but not unprimed macrophages largely excluded the activated form of IRF3 from the nucleus following bacterial infection. These data are consistent with a relationship of mutual inhibition between IRF3 and IFN-γ-activated programs, possibly as a component of a partially reversible mechanism for modulating the activity of potent innate immune effectors (such as Nos2) in the context of intracellular infection.
| S-EPMC9550582 | biostudies-literature
Project description:Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.
| S-EPMC4601085 | biostudies-literature