1. Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis
- Author
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Zhao Jianjun, Gao Xiaojuan, Xia Zhang, Yuanjie Li, Yue Tong, Yong Jingjiao, Wen Song, and Wang Hanqing
- Subjects
Adult ,Male ,Programmed cell death ,Adolescent ,Lipopolysaccharide ,Immunology ,Syk ,Pharmacology ,lcsh:RC346-429 ,Social Defeat ,Mice ,Young Adult ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Chalcone ,NLRP3 ,Glucosides ,Downregulation and upregulation ,NLR Family, Pyrin Domain-Containing 3 Protein ,Pyroptosis ,medicine ,Animals ,Humans ,Syk Kinase ,miRNA-27a ,lcsh:Neurology. Diseases of the nervous system ,Cells, Cultured ,biology ,Microglia ,Depression ,Chemistry ,Research ,General Neuroscience ,NF-kappa B ,NF-κB ,Middle Aged ,Mice, Inbred C57BL ,MicroRNAs ,medicine.anatomical_structure ,Animals, Newborn ,Neurology ,Isoliquiritin ,biology.protein ,Female ,NeuN - Abstract
Background The NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism. Methods Expression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-κB axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a. Results Our results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-κB, and NLRP3: cleaved Caspase-1, IL-1β, and GSDMD-N: and elevated the concentration of IL-1β, IL-6, and TNF-α, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-κB, NLRP3; cleaved Caspase-1, IL-1β, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-κB axis controlled decrease of pyroptosis via NLRP3 cascade.
- Published
- 2021