Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis

作者：Shijie Li, Dan‐dan Ruan, Weizhen Wu, Min Wu, Qiuyan Wu, Hanlu Wang, Yuanyuan Ji, Yanping Zhang, Xin-fu Lin, Zhu-ting Fang, Lisheng Liao, Jie-wei Luo, Mei-zhu Gao, Jiabin Wu · 发表于：Pediatric Rheumatology · 年份：2023 · DOI：10.1186/s12969-023-00909-5 · 被引用次数：16 · 研究领域：Systemic Lupus Erythematosus Research、Immune Response and Inflammation、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Abstract Objectives Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+plasma cells subset (PCs) in LN. Methods C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin–eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+PC subsets in the blood and kidneys of mice were determined by flow cytometry. Results In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1β and TNFα). These cytokines were negatively correlated with ...