Abstract
BackgroundDepression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Patients with severe depression have suicidal tendencies. Exosomes are small vesicles released by the fusion of a multivesicular body and membranes, and they contain specific proteins, nucleic acids, and lipids related to the cells from which they originate. MicroRNAs (miRNAs) are 20–24 nt RNAs that can be packaged into exosomes and can play important regulatory roles. Astrocytes are the most abundant cell population in the central nervous system and have a close link to depression. Astrocyte activation could result in the release of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, which could promote the symptoms of depression. In previous research, our team confirmed that NK cells regulate depression in mice. Here, we propose that miRNA in the exosomes from NK cells performs this antidepressant function.MethodsExosomes from NK cells were shown by in vivo and in vitro experiments to alleviate symptoms of chronic mild stress in mice and decrease pro-inflammatory cytokines release from astrocytes. The production of pro-inflammatory cytokines was assessed by ELISA. Microarray analysis was used to identify critical miRNAs. Luciferase reporter assays, qPCR, and other experiments were used to prove that exosomal miR-207 has an important role in alleviating the symptoms of stress in mice.ResultsMiRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiments showed that these exosomes decreased the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) released by astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be overexpressed in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling in astrocytes. MiR-207 could decrease the release of pro-inflammatory cytokines and inhibit expression of Tril in vitro. In vivo experiments revealed that exosomes with low miR-207 levels showed decreased antidepressant activity.ConclusionCollectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting Tril to inhibit NF-κB signaling in astrocytes.
Highlights
Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep
Collectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting TLR4 interactor with leucine-rich repeats (Tril) to inhibit NF-κB signaling in astrocytes
Exosomes released from NK cells We first determined if NK cells could secrete exosomes that could pass through the blood-brain barrier in vivo and be taken up by target cells
Summary
Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Depression is a mood disorder characterized by indifferent and slow thinking, which includes symptoms of psychomotor retardation and loss of interest in normal things [1]. It is a common and burdensome psychological disorder, and the World Health Organization predicts that it will be the disease with the second highest morbidity in 2020 [2]. IL-1β and TNF-α are important mediators of glial activation and neuronal damage They play important roles in regulating neuronal development, neuronal excitability, sleep, and neuroendocrine functions [11]. Astrocytes play an important role in depression; there are no antidepressant drugs that have been designed to target astrocytes
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