Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis

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.

Characterizing the NLRP3 Inflammasome in Mood Disorders: Overview, Technical Development, and Measures of Peripheral Activation in Adolescent Patients

“…We are increasingly understanding the role of inflammation in psychiatric disease [23,[31][32][33][34][35][36]. As evidenced by our literature overview, there is evidence to support upregulation of the NLRP3 inflammasome in mood disorders [24][25][26][27][28][29][30]. However, a lack of reliable measurement techniques in psychiatric conditions highlight the need for a robust assay, which may be used as a component of disease diagnosis and drug screening.…”

“…To date, we identified seven articles investigated NLRP3 inflammasome activation in neuropsychiatric patients suffering from mood disorders, including major depressive disorder (MDD) and bipolar disorder [24][25][26][27][28][29][30]. Across studies investigating these mood disorders, the techniques used to measure the NLRP3 inflammasome were real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme linked immunosorbent (ELISA), and Western blotting (Table 1).…”

MitoQ Is Able to Modulate Apoptosis and Inflammation

“…Moreover, previous studies have revealed IL-17 as a cytokine involved in chronic inflammatory neurological diseases, and we can confirm that, in our neuronal model, it can be modulated from the inflammation [ 52 , 53 ]. All these data are relevant for the proper understanding of cytokines signaling pathways involved in the regulation of neuroinflammation and could be crucial for the development of new therapeutical strategies [ 54 ].…”

Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury

“…The activation of the TLR4/NF-κB signaling pathway could modulate NLRP3 inflammasome activation in inflammatory bowel disease and induce GSDMD-mediated pyroptosis in tubular cells in diabetic kidney disease ( Chen et al, 2019 ; Wang Y. et al, 2019 ). Moreover, SYK expression which was downregulated by the activation of miRNA-27a could stimulate the NF-κB signaling pathway and facilitate NLRP3-mediated pyroptosis ( Li et al, 2021 ). The previous study has shown that EE could regulate the expression of HMGB1 and mediate post-stroke angiogenesis ( Chen J.Y.…”