Department of Bone and Joint Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China.
Department of Dermatology, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China.
Cell Cycle. 2024 Jan;23(1):1-14. doi: 10.1080/15384101.2024.2304508. Epub 2024 Jan 17.
Rheumatoid arthritis (RA) is an inflammatory disease which causes severe pain and disability. Neutrophils play essential roles in the onset and progression of RA; thus, inhibition of neutrophil activation is becoming a popular therapeutic strategy. Dehydroandrographolide has provided satisfactory outcomes in inflammatory diseases; however, its therapeutic effects and mechanism in RA are not fully understood. Leukocyte mono-immunoglobulin-like receptor 3 (LMIR3) is a negative regulator highly expressed in neutrophils. To determine whether dehydroandrographolide negatively regulated neutrophils activation via LMIR3, cytokines release and collagen-induced arthritis (CIA) rats were used and . Biacore, molecular docking analysis and molecular dynamics simulation were performed to prove the target of dehydroandrographolide. Moreover, the downstream signaling pathways of LMIR3 activation were analyzed by western blotting. Results showed that oral dehydroandrographolide administration of 2 mg/kg/day to CIA rats attenuated synovitis and bone and cartilage damage after the 28-day intervention, revealed using HE sections and micro-CT. Dehydroandrographolide significantly inhibited cytokine release and chemotaxis of LPS/TNF-α-activated neutrophils . Dehydroandrographolide inhibited neutrophils activation via binding to LMIR3. Moreover, dehydroandrographolide up-regulated the phosphorylation of SHP-1 and SHP-2, which are the essential kinases in the LMIR3 signaling pathways. This study revealed that dehydroandrographolide attenuated collagen-induced arthritis by suppressing neutrophil activation via LMIR3.
类风湿关节炎（RA）是一种炎症性疾病，可导致严重疼痛和残疾。中性粒细胞在 RA 的发病和进展中起重要作用；因此，抑制中性粒细胞的激活正成为一种热门的治疗策略。去氢穿心莲内酯在炎症性疾病中提供了令人满意的结果；然而，其在 RA 中的治疗效果和机制尚不完全清楚。白细胞单免疫球蛋白样受体 3（LMIR3）是一种在中性粒细胞中高度表达的负调节剂。为了确定去氢穿心莲内酯是否通过 LMIR3 负调控中性粒细胞的激活，使用细胞因子释放和胶原诱导关节炎（CIA）大鼠进行了研究。Biacore、分子对接分析和分子动力学模拟用于证明去氢穿心莲内酯的靶标。此外，通过 Western blot 分析了 LMIR3 激活的下游信号通路。结果表明，在 CIA 大鼠中，每天口服 2mg/kg 的去氢穿心莲内酯可减轻 28 天后的滑膜炎症和骨与软骨损伤，通过 HE 切片和 micro-CT 观察到。去氢穿心莲内酯可显著抑制 LPS/TNF-α 激活的中性粒细胞的细胞因子释放和趋化作用。去氢穿心莲内酯通过与 LMIR3 结合抑制中性粒细胞的激活。此外，去氢穿心莲内酯上调了 LMIR3 信号通路中的 SHP-1 和 SHP-2 的磷酸化，这是该信号通路中的必需激酶。本研究表明，去氢穿心莲内酯通过抑制 LMIR3 抑制中性粒细胞的激活，从而减轻胶原诱导性关节炎。
