M1 microglia-derived exosomes promote A1 astrocyte activation and aggravate ischemic injury via miR-331-5p/MAVS/NF-kB pathway
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PROVIDER: PRJNA1119183 | ENA |
REPOSITORIES: ENA
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Project description:Ischemic stroke (IS) is one of the most serious neurological diseases, characterized by high mortality and disability rates. Glia cells, particularly microglia and astrocytes, occupy a pivotal position in the progression of IS. In response to stroke, microglia undergo polarization, transforming into either pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype. Analogously, astrocytes would polarize to pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype. It has been documented that A1 astrocytes can be activated by M1 microglia, although precise underlying mechanism remains elusive. In our study, we emulated ischemic injury using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary astrocytes. Our findings revealed that M1 microglia could activate A1 astrocytes by secreting exosomes. According to RNA sequencing, circSTRN3 was enriched in M1 microglia-derived exosomes. Based on the review of literature and bioinformatics analysis, it was suggested that circSTRN3 could sponge miR-331-5p, while miR-331-5p could bind to MAVS and participate in the activation of NF-kB pathway and A1 astrocytes. Western blotting and qRT-PCR experiments verified this process. Furtherly, overexpression of circSTRN3 could aggravate neurological deficits, increase infarct volume, and promote cell death in MCAO/R model, whereas miR-331-5p inhibited this process. Furthermore, we conducted tests on circSTRN3 and miR-331-5p in exosomes isolated from the peripheral blood of IS patients, thereby confirming the correlation among circSTRN3, miR-331-5p, and the stroke severity score. Taken together, our study indicated that M1 microglia-derived exosomes could promote A1 astrocyte activation and exacerbate ischemic brain injury through the circSTRN3-miR331-5P/MAVS/NF-KB pathway.
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Project description:We found that fuse ΔLMP1 to MAVS could strengthen MAVS mediated inhibition of PRRSV replication in MARC-145 cells. To better understand the biological function of the fusion protein ΔLMP1-MAVS, overall gene expression of MARC-145 cells transfected with ΔLMP1-MAVS or MAVS was evaluated by mRNA-seq. The result showed that ΔLMP1-MAVS upregulated a number of genes associated with innate immune responses to viral infection, including plenty of interferon-stimulated genes. This study provides reference date to research the working mechanism of ΔLMP1-MAVS.
2019-03-05 | GSE111530 | GEO
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Project description:Innate immunity serves as the primary defense against viral and microbial infections in humans. Among its components, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-characterized intracellular pattern-recognition proteins that trigger innate immune responses upon viral infection. However, the precise influence of cellular metabolites, especially fatty acids, on the regulation of RLR-mediated antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a crucial metabolite responsible for modulating antiviral infections. Mechanistically, PA induces the palmitoylation of MAVS, leading to MAVS aggregation and subsequent activation, thereby enhancing the innate immune response against viral infections. Functionally, the enzyme palmitoyl-transferase ZDHHC24 plays a key role in catalyzing the palmitoylation of MAVS at both C46 and C79 residues, thereby facilitating the transduction of RLR-mediated TBK1-IRF3-IFN signaling pathway, particularly under conditions of PA stimulation or high-fat diet feeding. Conversely, the absence of ZDHHC24 significantly attenuates virus-induced innate immune responses in both cells and mice. Moreover, APT2 counteracts with ZDHHC24 to de-palmitoylate MAVS, thus inhibiting the antiviral response. Consequently, inhibition of APT2 using compounds like ML349 effectively reverses MAVS palmitoylation and activation in response to antiviral infections. These findings underscore the critical role of PA and ZDHHC24 in regulating antiviral innate immunity through MAVS palmitoylation, and suggest potential therapeutic strategies for combating viral infections, such as enhancing PA intake or specifically targeting APT2.
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Project description:BackgroundThe neuropathic pain with complex networks of neuroinflammatory activation severely limits clinical therapeutic research. TNF receptor-associated factor 6 (TRAF6) is associated with multiple inflammatory diseases. However, there remains confusion about the effects and mechanisms of TRAF6 in neuropathic pain.MethodsA chronic constriction injury (CCI) model was developed to simulate neuralgia in vivo. We overexpressed or knocked down TRAF6 in CCI mice, respectively. Activation of microglia by TRAF6, the inflammatory response, and disease progression were inspected using WB, qRT-PCR, immunofluorescence, flow cytometry, and ELISA assays. Moreover, the mechanism of M1/M2 polarization activation of microglia by TRAF6 was elaborated in BV-2 cells.ResultsTRAF6 was enhanced in the spinal neurons and microglia of the CCI mice model compared with the sham operation group.. Down-regulation of TRAF6 rescued the expression of Iba-1. In response to mechanical and thermal stimulation, PWT and PWL were improved after the knockdown of TRAF6. Decreased levels of pro-inflammatory factors were observed in TRAF6 knockdown groups. Meanwhile, increased microglial M1 markers induced by CCI were limited in mice with TRAF6 knockdown. In addition, TRAF6 overexpression has the precise opposite effect on CCI mice or microglia polarization. We also identifed that TRAF6 activated the c-JUN/NF-kB pathway signaling; the inhibitor of c-JUN/NF-kB could effectively alleviate the neuropathic pain induced by upregulated TRAF6 in the CCI mice model.ConclusionIn summary, this study indicated that TRAF6 was concerned with neuropathic pain, and targeting the TRAF6/c-JUN/NF-kB pathway may be a prospective target for treating neuropathic pain.
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Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.
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