1. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. 2. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, China; Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei, China. 3. Department of orthopedics, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China. 4. Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China. #These authors contributed equally.
✉ Corresponding authors: Prof. Hua WANG and Prof. Ling-ling ZHANG. E-mail address: wanghuaedu.cn (H. WANG); ll-zhangcom (L.L. ZHANG). Phone: +86-0551-6516-1206; Fax: +86-0551-6516-1208.
Citation:
Zhang X, Zhang Z, Zhao Y, Jin L, Tai Y, Tang Y, Geng S, Zhang H, Zhai Y, Yang Y, Pan P, He P, Fang S, Sun C, Chen Y, Zhou M, Liu L, Wang H, Xu L, Zhang T, Hua J, Wang H, Zhang L. Sodium chloride promotes macrophage pyroptosis and aggravates rheumatoid arthritis by activating SGK1 through GABA receptors Slc6a12. Int J Biol Sci 2024; 20(8):2922-2942. doi:10.7150/ijbs.93242. https://www.ijbs.com/v20p2922.htm
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and the production of autoantibodies. Previous studies have indicated an association between high-salt diets (HSD) and an increased risk of RA, yet the underlying mechanisms remain unclear. Macrophage pyroptosis, a pro-inflammatory form of cell death, plays a pivotal role in RA. In this study, we demonstrate that HSD exacerbates the severity of arthritis in collagen-induced arthritis (CIA) mice, correlating with macrophage infiltration and inflammatory lesions. Given the significant alterations observed in macrophages from CIA mice subjected to HSD, we specifically investigate the impact of HSD on macrophage responses in the inflammatory milieu of RA. In our in vitro experiments, pretreatment with NaCl enhances LPS-induced pyroptosis in RAW.264.7 and THP-1 cells through the p38 MAPK/NF-κB signaling pathway. Subsequent experiments reveal that Slc6a12 inhibitors and SGK1 silencing inhibit sodium-induced activation of macrophage pyroptosis and the p38 MAPK/NF-κB signaling pathway, whereas overexpression of the SGK1 gene counteracts the effect of sodium on macrophages.
In conclusion, our findings verified that high salt intake promotes the progression of RA and provided a detailed elucidation of the activation of macrophage pyroptosis induced by sodium transportation through the Slc6a12 channel.
Zhang X, Zhang Z, Zhao Y, Jin L, Tai Y, Tang Y, Geng S, Zhang H, Zhai Y, Yang Y, Pan P, He P, Fang S, Sun C, Chen Y, Zhou M, Liu L, Wang H, Xu L, Zhang T, Hua J, Wang H, Zhang L. Sodium chloride promotes macrophage pyroptosis and aggravates rheumatoid arthritis by activating SGK1 through GABA receptors Slc6a12. Int J Biol Sci 2024; 20(8):2922-2942. doi:10.7150/ijbs.93242. https://www.ijbs.com/v20p2922.htm
CSE
Zhang X, Zhang Z, Zhao Y, Jin L, Tai Y, Tang Y, Geng S, Zhang H, Zhai Y, Yang Y, Pan P, He P, Fang S, Sun C, Chen Y, Zhou M, Liu L, Wang H, Xu L, Zhang T, Hua J, Wang H, Zhang L. 2024. Sodium chloride promotes macrophage pyroptosis and aggravates rheumatoid arthritis by activating SGK1 through GABA receptors Slc6a12. Int J Biol Sci. 20(8):2922-2942.
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