溶质载体家族7成员11（SLC7A11）通过调节白细胞介素-17（IL-17）通路抑制细胞焦亡，从而减轻类风湿性关节炎的发展。

SLC7A11 suppresses pyroptosis to alleviate rheumatoid arthritis development by modulating the IL-17 pathway.

作者信息

Chen Shaojian, Zou Longqiang, Huang Liangcai, Li Zhengnan, Zeng Hui, Zeng Yanmei, Wu Juan

机构信息

Department of Sports Medical Ganzhou People's Hospital/The Affiliated Ganzhou Hospital Jiangxi Medical College Nanchang University Ganzhou China.

出版信息

Int Immunopharmacol. 2025 Feb 6;147:114019. doi: 10.1016/j.intimp.2025.114019. Epub 2025 Jan 10.

DOI:10.1016/j.intimp.2025.114019

PMID:39798470

Abstract

BACKGROUND

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (SLC7A11) influences RA development.

METHODS

Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro.

RESULTS

CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL-17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of SLC7A11 on inflammation, oxidative stress, and pyroptosis.

CONCLUSION

SLC7A11 suppresses pyroptosis to alleviate RA development by inhibiting the IL-17 pathway.

摘要

背景

类风湿关节炎（RA）是一种病因不明的自身免疫性疾病。本研究旨在探讨溶质载体家族7成员11（SLC7A11）影响RA发展的潜在机制。

方法

构建胶原诱导性关节炎（CIA）小鼠模型，观察疾病发作情况及病理评分。采用苏木精-伊红染色和番红O-固绿染色检查病理变化。使用酶联免疫吸附测定法（ELISA）检测乳酸脱氢酶（LDH）、炎性细胞因子（肿瘤坏死因子[TNF]-α、白细胞介素[IL]-18和IL-1β）以及氧化应激（活性氧、丙二醛和谷胱甘肽）水平。进行蛋白质免疫印迹法检测细胞焦亡及相关通路蛋白的表达。用TNF-α处理RA患者的成纤维样滑膜细胞（RA-FLS）。分别通过划痕实验、Transwell实验和流式细胞术评估细胞迁移、侵袭和半胱天冬酶-1水平。利用生物信息学分析RA中SLC7A11与免疫细胞浸润之间的相关性。此外，筛选RA中SLC7A11的下游通路，并在体外验证SLC7A11对这些通路的影响。

结果

成功建立CIA小鼠模型，显示RA中SLC7A11显著下调。染色结果表明，SLC7A11过表达显著减轻CIA小鼠的关节损伤。体外实验表明，SLC7A11过表达抑制TNF-α诱导的RA-FLS的迁移、侵袭和半胱天冬酶-1表达水平。此外，SLC7A11抑制炎症、LDH释放和氧化应激，同时抑制细胞焦亡。SLC7A11在多种免疫细胞中的表达存在显著差异。IL-17通路被确定为SLC7A11的下游通路，且SLC7A11抑制IL-17通路蛋白的表达。此外，IL-17通路激活剂重组人IL-17A减弱了SLC7A11对炎症、氧化应激和细胞焦亡的抑制作用。