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Defective neutrophil-derived exosomes induce macrophage activation through miR-122-5p in Behçet’s Disease

ABSTRACT: Background Behçet’s disease (BD) is a life-threatening systemic vasculitis characterized by polymorphonuclear neutrophil (PMN) and macrophage activation. This study aimed to elucidate the potential dysregulation of BD PMN exosomes on macrophage activation. Methods BD PMN exosomes were isolated, quantified, incubated with macrophages, and analyzed by miRNA sequencing (n=4). RNA sequencing of miRNA-transfected macrophages (n=6) was analyzed using transcription factor co-regulation network and miRNA target prediction to identify key regulatory factors, which were validated by dual luciferase reporter assay and miRNA/siRNA transfection. Results BD PMN exosomes were decreased and negatively correlated with CRP. PMN exosomes suppressed IL-6, TNF-α, CD80 and CD86 expressions on macrophages, which were attenuated in BD PMN exosomes. miRNA sequencing showed decreased miR-122-5p in BD PMN exosomes, which targeted IRF5, suppressed TLR4 signaling and IFN-β autocrine, and downregulated macrophage activation. Conclusions BD PMN exosomes were decreased in both quantity and miR-122-5p, which impaired the immunoregulatory potential on macrophages through degrading IRF5 and suppressing IFN-β autocrine, indicating a new interaction mechanism between PMNs and macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252885 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

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Defective neutrophil-derived exosomes induce macrophage activation through miR-122-5p in Behçet’s Disease

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