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Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy.

ABSTRACT: The molecular development of diabetic encephalopathy remains ill-defined. Recently, we reported that elimination of inflammatory macrophages alleviated the progress and severity of diabetic encephalopathy. Here, we studied the underlying mechanism. Inflammatory macrophages were isolated from the brain of the mice that received i.p. injection of streptozotocin (STZ) to develop diabetes 6 weeks before, and showed enhanced autophagy activity, seemingly through augmentation of Beclin-1 levels. However, the increases in Beclin-1 levels did not result from enhanced gene transcription, but appeared to result from suppression of a Beclin-1-inhibitory microRNA, miR-384-5p. Overexpression of miR-384-5p in the inflammatory macrophages through an adeno-associated virus mediated gene transfer system significantly reduced inflammatory macrophages in the diabetic brain, resulting in attenuation of the STZ-induced decreases in brain malondialdehyde, catalase and superoxidase anion-positive cells, and the STZ-induced increases in brain nitric oxide. Thus, these data suggest that downregulation of miR-384-5p in the inflammatory macrophages may enhance macrophage autophagy and contribute to the development of diabetic encephalopathy, which may be suppressed by re-expression of miR-384-5p in macrophages.

SUBMITTER: Wang B

PROVIDER: S-EPMC5835816 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy.

Wang Beiyun B Huang Jing J Li Jingbo J Zhong Yuan Y

American journal of translational research 20180215 2

The molecular development of diabetic encephalopathy remains ill-defined. Recently, we reported that elimination of inflammatory macrophages alleviated the progress and severity of diabetic encephalopathy. Here, we studied the underlying mechanism. Inflammatory macrophages were isolated from the brain of the mice that received i.p. injection of streptozotocin (STZ) to develop diabetes 6 weeks before, and showed enhanced autophagy activity, seemingly through augmentation of Beclin-1 levels. Howev ...[more]

PMID: 29511445

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Project description:BackgroundRefractory diabetic wounds are a common occurrence in patients with diabetes and epidermis-specific macroautophagy/autophagy impairment has been implicated in their pathogenesis. Therefore, identifying and developing treatment strategies capable of normalizing epidermis-specific macroautophagy/autophagy could facilitate diabetic wound healing. The study aims to investigate the potential of bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) from hypoxic conditions as a treatment to normalize epidermis-specific autophagy for diabetic wound healing.MethodsWe compared the effects of bone marrow mesenchymal stem cell (BMSC)-sourced exosomes (BMSC-Exos) from hypoxic conditions to those of BMSC in normoxic conditions (noBMSC-Exos). Our studies involved morphometric assessment of the exosomes, identification of the microRNA (miRNA) responsible for the effects, evaluation of keratinocyte functions and examination of effects of the exosomes on several molecules involved in the autophagy pathway such as microtubule-associated protein 1 light chain 3 beta, beclin 1, sequestosome 1, autophagy-related 5 and autophagy-related 5. The experiments used human BMSCs from the American Type Culture Collection, an in vivo mouse model of diabetes (db/db) to assess wound healing, as well as the human keratinocyte HaCaT cell line. In the methodology, the authors utilized an array of approaches that included electron microscopy, small interfering RNA (siRNA) studies, RNA in situ hybridization, quantitative real-time reverse transcription PCR (qRT-PCR), the isolation, sequencing and differential expression of miRNAs, as well as the use of miR-4645-5p-specific knockdown with an inhibitor.ResultsHypoxia affected the release of exosomes from hypoxic BMSCs (hy-BMSCs) and influenced the size and morphology of the exosomes. Moreover, hyBMSC-Exo treatment markedly improved keratinocyte function, including keratinocyte autophagy, proliferation and migration. miRNA microarray and bioinformatics analysis showed that the target genes of the differentially expressed miRNAs were mainly enriched in 'autophagy' and 'process utilizing autophagic mechanism' in the 'biological process' category and miR-4645-5p as a major contributor to the pro-autophagy effect of hyBMSC-Exos. Moreover, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) was identified as a potential target of exosomal miR-4645-5p; this was confirmed using a dual luciferase assay. Exosomal miR-4645-5p mediates the inactivation of the MAPKAPK2-induced AKT kinase group (comprising AKT1, AKT2, and AKT3), which in turn suppresses AKT-mTORC1 signaling, thereby facilitating miR-4645-5p-mediated autophagy.ConclusionsOverall, the results of this study showed that hyBMSC-Exo-mediated transfer of miR-4645-5p inactivated MAPKAPK2-induced AKT-mTORC1 signaling in keratinocytes, which activated keratinocyte autophagy, proliferation and migration, resulting in diabetic wound healing in mice. Collectively, the findings could aid in the development of a novel therapeutic strategy for diabetic wounds.

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Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy.

Publications

Control of macrophage autophagy by miR-384-5p in the development of diabetic encephalopathy.

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