Ji Min Jeong, Ryu Hee Jung, Hong Jeong Hee
Department of Physiology, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.
Front Cell Dev Biol. 2021 Aug 31;9:700879. doi: 10.3389/fcell.2021.700879. eCollection 2021.
Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation of the synovial membrane ultimately leading to permanent damage in the affected joints. For this study, synovial fluids from 16 patients diagnosed with either RA or osteoarthritis (OA) were used to examine volume regulation and cooperative water channels, both of which are involved in the cytotoxic edema identified in RA-fibroblast-like synoviocytes (FLS). The osmolarity and inflammatory cytokine interleukin (IL)-6 of synovial fluids from RA patients were mildly enhanced compared to that from OA patients. RA-FLS demonstrated the enhanced property of regulatory volume increase in response to IL-6 and synovial fluids from RA patients. Although there was no difference in the protein expression of the volume-associated protein sodium-potassium-chloride cotransporter1 (NKCC1), its activity was increased by treatment with IL-6. Membrane localization of NKCC1 was also increased by IL-6 treatment. Additionally, both the protein and membrane expressions of aquaporin-1 were increased in RA-FLS by IL-6 stimulation. The IL-6-mediated enhanced osmotic sensitivity of RA-FLS likely involves NKCC1 and aquaporin-1, which mainly constitute the volume-associated ion transporter and water channel elements. These results suggest that RA-FLS provide enhanced electrolytes and concomitant water movement through NKCC1 and aquaporin-1, thereby inducing cellular swelling ultimately resulting in cytotoxic edema. Attenuation of cytotoxic edema and verification of its related mechanism will provide novel therapeutic approaches to RA treatment within the scope of cytotoxic edema.
类风湿性关节炎（RA）是一种自身免疫性疾病，会导致滑膜炎症，最终导致受影响关节的永久性损伤。在本研究中，使用了16名被诊断为RA或骨关节炎（OA）患者的滑液来检测容积调节和协同水通道，这两者都与RA成纤维细胞样滑膜细胞（FLS）中发现的细胞毒性水肿有关。与OA患者相比，RA患者滑液的渗透压和炎性细胞因子白细胞介素（IL）-6略有升高。RA-FLS表现出对IL-6和RA患者滑液反应时调节性容积增加的增强特性。尽管容积相关蛋白钠-钾-氯共转运体1（NKCC1）的蛋白表达没有差异，但其活性通过IL-6处理而增加。IL-6处理也增加了NKCC1的膜定位。此外，IL-6刺激使RA-FLS中水通道蛋白-1的蛋白和膜表达均增加。IL-6介导的RA-FLS渗透压敏感性增强可能涉及NKCC1和水通道蛋白-1，它们主要构成容积相关的离子转运体和水通道元件。这些结果表明，RA-FLS通过NKCC1和水通道蛋白-1提供增强的电解质和伴随的水移动，从而诱导细胞肿胀，最终导致细胞毒性水肿。减轻细胞毒性水肿并验证其相关机制将为细胞毒性水肿范围内的RA治疗提供新的治疗方法。
