Dataset Information

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury via Exosomal miR-let-7e.

ABSTRACT: Defective brain hormonal signaling and autophagy have been associated with neurodegeneration after brain insults, characterized by neuronal loss and cognitive dysfunction. However, few studies have linked them in the context of brain injury. Insulin-like growth factor-1 (IGF-1) is an important hormone that contributes to growth, cell proliferation, and autophagy and is also expressed in the brain. Here, we assessed the clinical data from TBI patients and performed both in vitro and in vivo experiments with proteomic and gene-chip analysis to assess the functions of IGF-1 in mitophagy following TBI. We show that reduced plasma IGF-1 is correlated with cognition in TBI patients. Overexpression of astrocytic IGF-1 improves cognitive dysfunction and mitophagy in TBI mice. Mechanically, proteomics data show that the IGF-1-related NF-κB pathway transcriptionally regulates decapping mRNA2 (Dcp2) and miR-let-7, together with IGF-1R to orchestrate mitophagy in TBI. Finally, we demonstrate that brain injury induces impaired mitophagy at the chronic stage and that IGF-1 treatment could facilitate the mitophagy markers via exosomal miR-let-7e. By showing that IGF-1 is an important mediator of the beneficial effect of the neural-endocrine network in TBI models, our findings place IGF-1/IGF-1R as a potential target capable of noncoding RNAs and opposing mitophagy failure and cognitive impairment in TBI.

SUBMITTER: Dabin R

PROVIDER: S-EPMC9433209 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury via Exosomal miR-let-7e.

Dabin Ren R Wei Chen C Liang Shu S Ke Cao C Zhihan Wang W Ping Zheng Z

Oxidative medicine and cellular longevity 20220824

Defective brain hormonal signaling and autophagy have been associated with neurodegeneration after brain insults, characterized by neuronal loss and cognitive dysfunction. However, few studies have linked them in the context of brain injury. Insulin-like growth factor-1 (IGF-1) is an important hormone that contributes to growth, cell proliferation, and autophagy and is also expressed in the brain. Here, we assessed the clinical data from TBI patients and performed both in vitro and in vivo exper ...[more]

PMID: 36062186

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Project description:BackgroundExosomes may contain excess cellular components released by cells in response to harmful external stimuli to maintain cellular homeostasis. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), can induce cell apoptosis, alter cellular component expression levels, and stimulate exosome release. In this study, we examined whether exosomes released from nucleus pulposus cells (NPCs) under inflammatory conditions could induce normal NP cell apoptosis in rats and its underlining mechanism.MethodsExosomes were isolated from TNF-α-treated NPCs and used to treat normal NPCs. The effects were assessed by flow cytometry and western blot analysis. Anti-apoptotic insulin-like growth factor-1 (IGF-1) expression in NPCs was assessed by western blot analysis. Given the exosomal miRNAs might be the key factors of exosomes, bioinformatics approaches and quantitative real-time polymerase chain reaction (qRT-PCR) were used to identify IGF-1-regulating micro RNAs (miRNAs), including miR-16. Luciferase reporter assay assessed miR-16 regulation of IGF-1 and IGF-1 receptor (IGF-1R). NPCs were transfected with miR-16 mimic, and exosomes were applied to normal NPCs. NPCs were pretreated with 10 ng/mL TNF-α, transfected with miR-16 inhibitors, and the exosomes were isolated. Cell and exosome miR-16 levels were detected by qRT-PCR. Western blot analysis determined IGF-1, IGF-1R, and apoptotic marker levels in exosome-treated NPCs.ResultsExosomes from TNF-α-treated NPCs induced apoptosis in normal NPCs and repressed IGF-1 expression. Exosomal miR-16 regulated IGF-1 and induced NPC apoptosis. The dual-luciferase reporter assay revealed that miR-16 binds the 3' untranslated regions (3'-UTRs) of IGF-1 and IGF-1R. Exosomal miR-16 repressed IGF-1 and the IGF-1R/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway which therefore induced NPC apoptosis. Rescue experiments using miR-16 inhibitors further validated these findings.ConclusionsThe inflammatory factor TNF-α stimulated exosome release from NPCs, which induced the apoptosis of normal NPCs through the actions of exosomal miR-16. Exosomal miR-16 directly repressed the anti-apoptotic IGF-1/IGF-1R pathway, increasing the apoptosis of NPCs.

Project description:BACKGROUND: Psoriasis is a complex disease at the cellular, genomic and genetic levels. The role of microRNAs in skin development was shown in a keratinocyte-specific Dicer knockout mouse model. Considering that two main characteristics of psoriasis are keratinocytes hyperproliferation and abnormal skin differentiation, we hypothesized that aberrant microRNA expression contributes to the psoriatic phenotype. Here, we describe the differential expression of miRNAs in psoriatic involved and uninvolved skin as compared to normal skin, revealing an additional aspect of this complex disorder. METHODOLOGY/PRINCIPAL FINDINGS: Expression arrays were used to compare microRNA expression in normal skin versus psoriatic involved and uninvolved skin. Fourteen differentially expressed microRNAs were identified, including hsa-miR-99a, hsa-miR-150, hsa-miR-423 and hsa-miR-197. The expression of these microRNAs was reevaluated by qPCR. IGF-1R, which is involved in skin development and the pathogenesis of psoriasis, is a predicted target of hsa-miR-99a. In an in situ hybridization assay, we found that IGF-1R and miR-99a are reciprocally expressed in the epidermis. Using a reporter assay, we found that IGF-1R is targeted by hsa-miR-99a. Moreover, over expression of miR-99a in primary keratinocytes down-regulates the expression of the endogenous IGF-1R protein. Over expression of miR-99a also inhibits keratinocyte proliferation and increases Keratin 10 expression. These findings suggest that overexpression of hsa-miR-99a in keratinocytes drives them towards differentiation. In primary keratinocytes grown in high Ca(++), miR-99a expression increases over time. Finally, we found that IGF1 increases the expression of miR-99a. CONCLUSIONS/SIGNIFICANCE: We identified several microRNAs that are expressed differentially in normal and psoriatic skin. One of these miRNAs is miR-99a that regulates the expression of IGF-1R. Moreover, miR-99a seems to play a role in the differentiation of keratinocytes. We suggest that miR-99a is one of the regulators of the IGF-1R signaling pathway in keratinocytes. Activation of IGF1 signaling results in elevation of miR-99a which represses the expression of IGF-1R.

Dataset Information

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury via Exosomal miR-let-7e.

Publications

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury via Exosomal miR-let-7e.

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