Chen Huan, Pan Ting, Liu Panwang, Wang Ping, Xu Shijun
Institute of Material Medical Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Evid Based Complement Alternat Med. 2019 Dec 26;2019:3258572. doi: 10.1155/2019/3258572. eCollection 2019.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. Succinate is an inflammatory metabolic signal that exacerbates RA synovitis by activating succinate receptor 1 (SUCNR1) to amplify the release of IL-1. Thus, inhibition of succinate activation of SUCRN1 could be an effective method to inhibit the inflammation of RA. Baihu Jia Guizhi decoction (BHGZ), which is composed of , Bge., Presl., Fisch., and L., is a Traditional Chinese Medicine (TCM) prescription used to treat RA in clinic. In addition, TCM believes that damp and heat environment is one of the causes of RA. In this study, we tested the role of damp and heat environments in exacerbating RA inflammation and the anti-inflammatory effect of BHGZ, based on succinate/SUCNR1/IL-1 pathway in the adjuvant arthritis (AA) model with damp and heat environment (AA + DHE). Results showed that paw swelling and synovial pathology were significantly increased in AA rats, and these results were aggravated by stimulation in damp and heat environment. BHGZ improved AA + DHE rats' paw swelling, synovial hyperplasia, and inflammatory cell infiltration and reduced IL-1. In addition, AA rats significantly increased the expression of SUCNR1, and the stimulation of damp and heat environment not only increased the expression of SUCNR1 but also promoted the accumulation of succinate. BHGZ simultaneously reduced the concentration of succinate and the expression of SUCNR1. Finally, SDH activity was decreased in AA rats and AA + DHE rats, while BHGZ increased SDH activity and then reduced succinate concentration. Therefore, we prove that damp and heat environment deteriorated the inflammation of RA which is the activation of succinate/SUCNR1 pathway, while BHGZ regulates SDH activity to reduce the accumulation of succinate and inhibit the activation of SUCNR1 that is the underlying mechanism of its treatment of RA.
类风湿性关节炎（RA）是一种以滑膜炎为特征的自身免疫性疾病。琥珀酸是一种炎症代谢信号，通过激活琥珀酸受体1（SUCNR1）来放大白细胞介素-1（IL-1）的释放，从而加剧RA滑膜炎。因此，抑制琥珀酸对SUCRN1的激活可能是抑制RA炎症的有效方法。白虎加桂枝汤（BHGZ）由石膏、知母、甘草、粳米、桂枝组成，是临床上用于治疗RA的中药方剂。此外，中医认为湿热环境是RA的病因之一。在本研究中，我们基于湿热环境佐剂性关节炎（AA）模型（AA + DHE）中的琥珀酸/SUCNR1/IL-1通路，测试了湿热环境在加剧RA炎症中的作用以及BHGZ的抗炎作用。结果表明，AA大鼠的足肿胀和滑膜病理显著增加，并且在湿热环境刺激下这些结果加剧。BHGZ改善了AA + DHE大鼠的足肿胀、滑膜增生和炎性细胞浸润，并降低了IL-1水平。此外，AA大鼠中SUCNR1的表达显著增加，湿热环境刺激不仅增加了SUCNR1的表达，还促进了琥珀酸的积累。BHGZ同时降低了琥珀酸浓度和SUCNR1的表达。最后，AA大鼠和AA + DHE大鼠的琥珀酸脱氢酶（SDH）活性降低，而BHGZ增加了SDH活性，进而降低了琥珀酸浓度。因此，我们证明湿热环境通过激活琥珀酸/SUCNR1通路使RA炎症恶化，而BHGZ通过调节SDH活性来减少琥珀酸积累并抑制SUCNR1的激活，这是其治疗RA的潜在机制。
