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M1 microglia-derived exosomes promote A1 astrocyte activation and aggravate ischemic injury via miR-331-5p/MAVS/NF-kB pathway

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE268852 | GEO | 2024/12/04

REPOSITORIES: GEO

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Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.

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M1 microglia-derived exosomes promote A1 astrocyte activation and aggravate ischemic injury via miR-331-5p/MAVS/NF-kB pathway

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