芳香烃受体(AhR)激活改善LPS诱导的小鼠抑郁样行为

Activation of aryl hydrocarbon receptor(AhR)alleviates depressivelike behaviors in LPS-induced mice

芳香烃受体(aryl hydrocarbon receptor,AhR)在调节氧化应激和免疫反应中的作用越来越被人们所认识,但它在抑郁症中的作用和潜在机制仍不明了。本研究旨在研究内源性AhR配体6-甲酰基吲哚并[3,2-b]咔唑(6-formylindolo[3,2-b]carbazole,FICZ)对脂多糖(lipopolysaccharide,LPS)诱导的小鼠抑郁症模型的作用及其机制。FICZ(50 mg/kg)处理后,雄性C57BL/6J小鼠腹膜内注射LPS,并在24 h后进行行为学试验。用酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测小鼠海马和血清中炎症细胞因子(IL-6、IL-1β和TNF-α)浓度,用qPCR和Western blot检测小鼠海马CYP1A1、AhR和NLRP3表达变化。结果显示,相比对照组,单独LPS处理显著下调小鼠海马CYP1A1 mRNA和AhR蛋白表达水平,降低小鼠糖水偏好,延长强迫游泳试验中静止不动时间,提高小鼠海马IL-6和IL-1β水平,提高小鼠血清IL-1β水平,上调小鼠海马NLRP3 mRNA和蛋白表达水平,而FICZ可显著逆转LPS的上述作用。以上结果提示,AhR激活可减弱与抑郁症相关的炎症反应,其机制是下调炎症小体关键成分NLRP3的表达。本研究为AhR在抑郁症发病机制中的作用提供了新的见解,提示AhR是治疗抑郁症的潜在靶点。

The role of the aryl hydrocarbon receptor(AhR)in regulating oxidative stress and immune responses has been increasingly recognized.However,its involvement in depression and the underlying mechanisms remain poorly understood.This study aimed to investigate the effect of 6-formylindolo[3,2-b]carbazole(FICZ),an endogenous AhR ligand,on a lipopolysaccharide(LPS)-induced depression model and the underlying mechanism.After being treated with FICZ(50 mg/kg),male C57BL/6J mice received intraperitoneal injection of LPS and underwent behavioral tests 24 h later.The levels of inflammatory cytokines,including IL-1β,IL-6,and TNF-α,were measured in the hippocampus and serum using enzyme-linked immunosorbent assay(ELISA).The expression levels of CYP1A1,AhR and NLRP3 were analyzed using qPCR and Western blot.The results showed that,compared with control group,LPS alone significantly down-regulated the expression levels of CYP1A1 mRNA and AhR protein in the hippocampus of mice,reduced glucose preference,prolonged immobility time in forced swimming test,increased IL-6 and IL-1βlevels in the hippocampus,increased serum IL-1βlevel,and up-regulated NLRP3 mRNA and protein expression levels in mouse hippocampus,while FICZ significantly reversed the aforementioned effects of LPS.These findings suggest that AhR activation attenuates the inflammatory response associated with depression and modulates the expression of NLRP3.The present study provides novel insights into the role of AhR in the development of depression,and presents AhR as a potential therapeutic target for the treatment of depression.