Systemic Lupus Erythematosus Stimulates Chondrocyte Pyroptosis to Aggravate Arthritis via Suppression of NRF-2/KEAP-1 and NF-κB Pathway

Shuchao Shen,1,&ast; Xuliang Fang,1,&ast; Helou Zhang,1,&ast; Tingting Lang,2,&ast; Fangda Fu,1 Yu Du,3 Taotao Xu,4 Hongting Jin,1 Peijian Tong,4 Chengliang Wu,1 Changfeng Hu,3 Hongfeng Ruan1,&ast; 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310053, People’s Republic of China; 2School of Information and Electronic Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang, 310023, People’s Republic of China; 3College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 4Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel +8615869006032 ; +8613175007759, Email [email protected]; [email protected]: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations, including joint symptoms. Arthritis represents one of the earliest manifestations of SLE, profoundly affecting the quality of life for affected individuals, yet the underlying mechanisms of SLE-associated arthritis remain insufficiently investigated. The study aimed to investigate the impact of SLE exacerbation on arthritis using the MRL/lpr mouse model, which closely mimics human SLE manifestations.Methods: In the present study, we evaluated the impact of SLE onset on knee joint degeneration by comparing arthritic phenotype and complex molecular alterations between 6 female 14-week-old MRL/lpr mice, which manifest SLE, and MRL/MpJ mice, which remain unaffected.Results: Our results demonstrated that MRL/lpr mice exhibited a more severe arthritic phenotype compared to MRL/MpJ mice, characterized by elevated Osteoarthritis Research Society International (OARSI) scores (P < 0.01), disrupted extracellular matrix metabolism, impaired chondrocyte proliferation and increased apoptosis. Notably, inflammatory cytokines proteins such as IL-1β and TNF-α (both P < 0.01), IL-18 and IL-6 (both P < 0.05), were significantly increased in articular cartilage of MRL/lpr mice, accompanied by increased expression of calcitonin gene-related peptide (CGRP) (P < 0.05), NETRIN-1, and NESTIN (both P < 0.01), indicating that SLE promotes inflammation response and sensory nerve ingrowth in the knee joint, contributing to the progression of arthritis. Mechanistic analysis revealed that SLE exacerbation intensified chondrocyte pyroptosis by upregulating pyroptotic-related proteins, including NLRP3, CASPASE-1, and gasdermin D (all P < 0.01), through the regulation of the nuclear factor erythroid 2-related factor (NRF-2)/KEAP-1 and nuclear factor kappa-B (NF-κB) pathway.Conclusion: Collectively, our findings underscore the mechanistic connection between chondrocyte pyroptosis and arthritis exacerbation in SLE, suggesting potential therapeutic targets for mitigating arthritis progression in the context of SLE.Keywords: systemic lupus erythematosus, arthritis, chondrocyte, pyroptosis, NRF-2/KEAP-1 pathway