Choi Yunjung, Jung Ji-Hyun, Lee Eun-Gyeong, Kim Kyoung Min, Yoo Wan-Hee
Division of Rheumatology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Jeollabukdo 54907, Republic of Korea.
Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Jeollabukdo 54907, Republic of Korea.
Exp Ther Med. 2021 May;21(5):460. doi: 10.3892/etm.2021.9891. Epub 2021 Mar 3.
Impaired function of regulatory T cells (Tregs) contributes to the pathogenesis of systemic lupus erythematosus (SLE). Our previous study demonstrated aberrant responses of T lymphocytes to endoplasmic reticulum (ER) stress in patients with SLE. The present study investigated whether ER stress inhibition by 4-phenylbutyric acid (4-PBA) ameliorated lupus manifestations in an experimental lupus model and the effect of ER stress inhibition on the frequency and function of Tregs. A murine lupus model was induced through a 4-week treatment with Resiquimod, a toll-like receptor (TLR) 7 agonist. From the 8th week, the mice were treated with 4-PBA for 4 weeks. 4-PBA significantly decreased the levels of anti-dsDNA antibodies and serum TNF-α. A significant decrease in glomerulonephritis score was also observed in the 4-PBA-treated group. ER stress inhibition decreased the activated T and B lymphocytes population of splenocytes; however, the population of Tregs was not significantly different between the vehicle and 4-PBA group. However, a markedly enhanced suppressive capacity of Treg was detected in the 4-PBA-treated group. The present results suggest that ER stress inhibition attenuated disease activity in an experimental model by improving the suppressive capacity of Tregs. Therefore, reduction of ER stress could be used as a beneficial therapeutic strategy in SLE.
调节性T细胞（Tregs）功能受损促成了系统性红斑狼疮（SLE）的发病机制。我们之前的研究表明，SLE患者的T淋巴细胞对内质网（ER）应激反应异常。本研究调查了4-苯基丁酸（4-PBA）抑制ER应激是否能改善实验性狼疮模型中的狼疮表现，以及ER应激抑制对Tregs频率和功能的影响。通过用Toll样受体（TLR）7激动剂瑞喹莫德进行为期4周的治疗诱导建立小鼠狼疮模型。从第8周起，小鼠用4-PBA治疗4周。4-PBA显著降低了抗双链DNA抗体水平和血清肿瘤坏死因子-α水平。在4-PBA治疗组中还观察到肾小球肾炎评分显著降低。ER应激抑制降低了脾细胞中活化的T和B淋巴细胞数量；然而，在载体组和4-PBA组之间，Tregs数量没有显著差异。但是，在4-PBA治疗组中检测到Treg的抑制能力明显增强。目前的结果表明，ER应激抑制通过提高Tregs的抑制能力减轻了实验模型中的疾病活动。因此，减轻ER应激可作为SLE的一种有益治疗策略。
