Wang Min-Yuan, Li Jia-Mei, Wu Yi-Lin, Zhang Yi, Hu Ting, Su Wen-Jun, Feng Ji-Feng, Jiang Chun-Lei
Department of Stress Medicine, Faculty of Psychology and Mental Health, Naval Medical University, Shanghai 200043, China.
Department of Neurology, Navy 971st Hospital of PLA, Qingdao 266071, China.
Sheng Li Xue Bao. 2024 Jun 25;76(3):353-364.
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-1β levels in the hippocampus, increased serum IL-1β level, 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.
芳烃受体（AhR）在调节氧化应激和免疫反应中的作用已得到越来越多的认可。然而，其在抑郁症中的作用及潜在机制仍知之甚少。本研究旨在探讨内源性AhR配体6-甲酰基吲哚并[3,2-b]咔唑（FICZ）对脂多糖（LPS）诱导的抑郁症模型的影响及其潜在机制。雄性C57BL/6J小鼠经FICZ（50 mg/kg）处理后，腹腔注射LPS，并在24小时后进行行为测试。采用酶联免疫吸附测定（ELISA）法检测海马体和血清中炎症细胞因子IL-1β、IL-6和TNF-α的水平。采用qPCR和蛋白质免疫印迹法分析CYP1A1、AhR和NLRP3的表达水平。结果显示，与对照组相比，单独使用LPS可显著下调小鼠海马体中CYP1A1 mRNA和AhR蛋白的表达水平，降低葡萄糖偏好，延长强迫游泳试验中的不动时间，增加海马体中IL-6和IL-1β水平，增加血清IL-1β水平，并上调小鼠海马体中NLRP3 mRNA和蛋白表达水平，而FICZ可显著逆转LPS的上述作用。这些发现表明，AhR激活可减轻与抑郁症相关的炎症反应，并调节NLRP3的表达。本研究为AhR在抑郁症发生发展中的作用提供了新的见解，并提出AhR作为治疗抑郁症的潜在治疗靶点。
