非诺贝特对干燥综合征小鼠Treg细胞的免疫调节作用

Immunomodulatory effects of fenofibrate on Treg cells of mice with Sjögren’s syndrome

目的探讨过氧化物酶体增殖物激活受体α(PPAR-α)激动剂非诺贝特对干燥综合征小鼠Treg细胞的免疫调节作用。方法将14只15周龄雄性NOD小鼠随机分为模型组和非诺贝特组,每组7只。模型组小鼠给予标准饲料喂养,非诺贝特组小鼠予含0.3 g·kg^(-1)非诺贝特的标准饲料喂养。分别于治疗前及治疗后4周、8周进行泪液分泌试验及角膜荧光素钠染色。治疗后8周收集小鼠泪腺组织,HE染色观察小鼠泪腺病理变化,实时荧光定量PCR检测小鼠泪腺中叉头状蛋白P3(Foxp3)及白细胞介素(IL)-10 mRNA相对表达量,流式细胞仪检测脾脏中调节性T细胞(Treg细胞)比例。结果与模型组相比,治疗后4周、8周非诺贝特组小鼠角膜荧光素钠染色评分均显著降低(P=0.003、0.001),泪液分泌量均显著增加(P=0.016、0.000)。组织病理学观察发现,与模型组相比,治疗后8周非诺贝特组小鼠泪腺组织淋巴细胞浸润面积百分比显著降低,差异有统计学意义(P=0.002)。实时荧光定量PCR检测结果显示,与模型组相比,非诺贝特组小鼠泪腺中Foxp3及IL^(-1)0 mRNA相对表达量均明显升高,差异均有统计学意义(P=0.002、0.008);流式细胞仪检测结果发现,与模型组相比,非诺贝特组小鼠脾脏中Treg细胞比例明显升高,差异有统计学意义(P=0.003)。结论非诺贝特可以明显缓解小鼠干燥综合征干眼症状,其机制可能与增加Treg细胞比例有关。

Objective To investigate the immunomodulatory effect of peroxisome proliferators-activated receptor-α(PPAR-α)agonist fenofibrate on Treg cells in mice with Sjögren’s syndrome.Methods Fourteen 15-week-old male NOD mice were randomly divided into the model group and fenofibrate group,with 7 mice in each group.Mice in the model group were given regular chow,while mice in the fenofibrate group were given special chow containing 0.3 g·kg^(-1) fenofibrate.Schirmer test and corneal fluorescein sodium staining were performed before treatment,4 and 8 weeks after treatment.Bilateral lacrimal glands extracted at week 8 after treatment were processed by hematoxylin and eosin staining for histopathological examination.The relative mRNA expression levels of forkhead protein P3(Foxp3)and interleukin-10(IL^(-1)0)in the lacrimal glands were detected by quantitative real-time polymerase chain reaction(qRT-PCR).The proportion of regulatory T cells(Treg cells)in the spleen was assessed by flow cytometry.Results Four and eight weeks after fenofibrate treatment,the corneal fluorescein sodium staining score in the fenofibrate group was significantly decreased compared with the model group(P=0.003,0.001),while the tear secretion was evidently increased(P=0.016,0.000).Histopathological results showed that compared with the model group,the extent of lymphocytes infiltration in the lacrimal glands was significantly reduced in the fenofibrate group after 8 weeks of treatment,and the difference was statistically significant(P=0.002).qRT-PCR analysis results demonstrated that compared with the model group,relative mRNA expression levels of Foxp3 and IL^(-1)0 were obviously increased in the fenofibrate group,and the differences were statistically significant(P=0.002,0.008).Flow cytometry results revealed that compared with the model group,the proportion of Treg cells in the spleen of fenofibrate-treated mice was significantly higher,and the difference was statistically significant(P=0.003).Conclusion Fenofibrate has significant therapeutic effects on SS-related dry eye,which may be related to the increased proportion of Treg cells.