Abstract：
β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2-/- CMS group, these results of the β-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.
摘要：
β-arrestin2是一种在脑生理学和病理学中用于信号转导的通用蛋白。在这里，我们研究了β-arrestin2参与氟西汀治疗抑郁症的药理作用。使用野生型(WT)和β-arrestin2-/-小鼠建立慢性轻度应激(CMS)模型。行为结果表明，CMS小鼠在尾部悬吊试验和强迫游泳试验中表现出增加的不动时间，外周血促炎因子浓度升高，焦亡相关蛋白的表达增加，与CON组相比，海马中神经胶质原纤维酸性蛋白和Caspase1p10的共标记增加。用氟西汀(FLX)治疗改善了这些病症。然而,与β-arrestin2-/-CMS组相比，β-arrestin2-/-CMS+FLX组无明显变化。这些结果表明，通过敲除β-arrestin2可以消除FLX的上述作用。质谱表明FLX促进β-arrestin2与抑郁小鼠的NLRP2炎性体的结合。随后，细胞实验结果表明，5HT2B受体拮抗剂可能通过减弱NLRP2与β-arrestin2的结合来减弱L-犬尿氨酸ATP诱导的细胞焦亡。我们进一步发现β-arrestin2的缺乏消除了氟西汀的抗焦亡作用。总之,β-arrestin2是氟西汀减轻CMS小鼠海马星形胶质细胞焦亡的必需蛋白。机械上,我们发现5-HT2BR-β-arrestin2-NLRP2轴对于维持氟西汀的抗抑郁作用至关重要。
