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miR-122-5p Promotes Peripheral and Central Nervous System Inflammation in a Mouse Model of Intracerebral Hemorrhage via Disruption of the MLLT1/PI3K/AKT Signaling

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Abstract

Intracerebral hemorrhage (ICH) is a recognized central nervous system inflammation complication. Several microRNAs (miRNAs or miRs) have been documented to be vital modulators in peripheral and central nervous system inflammation. Based on whole transcriptome sequencing and bioinformatics analysis, this study aims to reveal the possible molecular mechanisms by which miR-122-5p affects the inflammatory response in the peripheral and central nervous system in a mouse model of ICH. Differentially expressed ICH-related miRNAs were screened. Adeno-associated viral vectors were used to knock down miR-122-5p in mice to evaluate the effect of miR-122-5p on peripheral and central nervous system inflammation. The downstream target gene of miR-122-5p was analyzed. Neurons were isolated from mice and treated with hemin to construct an in vitro model of ICH, followed by transduction with miR-122-5p mimic or combined with oe-MLLT1. The neurons were then co-cultured with microglia BV2 to assess their activation. It was found that miR-122-5p was highly expressed in ICH, and MLLT1 was lowly expressed. In vivo experiments showed that miR-122-5p knockdown decreased neurological deficits, BBB permeability, and inflammation in the peripheral and central nervous system in ICH mice. It involved its binding to MLLT1 and downregulation of the activity of the PI3K/AKT pathway. In vitro data exhibited that miR-122-5p stimulated the generation of inflammatory factors and microglia activation by targeting MLLT1 and inhibiting the PI3K/AKT pathway. Collectively, our work reveals a novel miR-122-5p/MLLT1-mediated regulatory network in ICH that may be a viable target for neuroinflammation alleviation.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Funding

This study was funded by Medical Research Project of Health Commission of Hebei Province in 2022 (20220084, Ning Yu).

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Ning Yu: Conceptualization, Investigation, Methodology, Funding acquisition, Writing - original draft, Writing - review & editing.Wenbin Tian: Data curation; Formal analysis, Software. Chao Liu: Data curation; Formal analysis, Software. Pei Zhang: Resources, Validation. Yinlong Zhao: Supervision, Validation, Visualization. Chengrui Nan: Visualization, Data curation. Qianxu Jin: Formal analysis, Writing - original draft, Writing - review & editing. Xiaopeng Li: Formal analysis, Writing - original draft, Writing - review & editing. Ya Liu: Conceptualization, Project administration, Writing - original draft, Writing - review & editing.

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Yu, N., Tian, W., Liu, C. et al. miR-122-5p Promotes Peripheral and Central Nervous System Inflammation in a Mouse Model of Intracerebral Hemorrhage via Disruption of the MLLT1/PI3K/AKT Signaling. Neurochem Res 48, 3665–3682 (2023). https://doi.org/10.1007/s11064-023-04014-7

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