Jiang Tingting, Liu Xuanqi, Wang Shumin, Chen Yu, Wang Yong, Li Xiaojing, Yao Genhong
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, 210008, China.
Free Radic Biol Med. 2025 Jun;233:355-364. doi: 10.1016/j.freeradbiomed.2025.03.043. Epub 2025 Mar 28.
Total glucosides of white paeony (TGP) has been used for treatment of Sjögren's syndrome (SS) patients. Paeoniflorin (PF) is the main active ingredient of TGP and has antioxidant and anti-inflammatory effects, but its underlying mechanism on SS remains to be explored. Aberrant activation of NLRP3 inflammasome can cause injury of submandibular gland (SG) in SS. However, whether PF regulates NLRP3 inflammasome activation in SS is unknown.
This study aims to investigate whether PF alleviated SS through suppressing NLRP3 inflammation activation and to explore the mechanism of PF in improving Sjögren-like symptoms in non-obese diabetic (NOD) mice.
The gene expression profiles of the labial gland (LG) between SS patients and non-SS patients were analyzed by bioinformatics. Non-obese diabetic (NOD) mice were selected as SS model. Mice were divided into normal saline group and two different doses of PF-treatment groups (50 and 100 mg/kg). The SS-like symptoms and pathological changes of submandibular gland (SG) were analyzed after 4 weeks of administration. SG cells were treated with or without PF and with or without ML385 (a specific inhibitor of Nrf2) in vitro, and then lipopolysaccharide(LPS) and adenosine triphosphate (ATP) were used to induce NLRP3 inflammasome activation in SG cells. Results NLRP3 was up-regulated in LG of SS patients and SG of SS mice. PF alleviated SS-like symptoms in SS mice. Compared with control group, NLRP3 and caspase-1 in the SG, and serum IL-1β and IL-18 of NOD mice were decreased in PF group. Furthermore, we found that PF inhibited NLRP3 activation via activating the Nrf2/HO-1 pathway in SG cells. In addition, we observed the activation of Nrf2/HO-1 in the SG of mice after PF administration.
Our findings suggested that PF inhibited NLRP3 inflammasome activation through regulating the Nrf2/HO-1 axis in SG of SS mice, which might be the underlying mechanism for the therapeutic effects of PF on SS.
白芍总苷（TGP）已用于治疗干燥综合征（SS）患者。芍药苷（PF）是TGP的主要活性成分，具有抗氧化和抗炎作用，但其对SS的潜在作用机制仍有待探索。NLRP3炎性小体的异常激活可导致SS患者下颌下腺（SG）损伤。然而，PF是否调节SS中NLRP3炎性小体的激活尚不清楚。
本研究旨在探讨PF是否通过抑制NLRP3炎症激活来缓解SS，并探讨PF改善非肥胖糖尿病（NOD）小鼠干燥样症状的机制。
通过生物信息学分析SS患者和非SS患者唇腺（LG）的基因表达谱。选择非肥胖糖尿病（NOD）小鼠作为SS模型。将小鼠分为生理盐水组和两种不同剂量的PF治疗组（50和100mg/kg）。给药4周后分析下颌下腺（SG）的干燥样症状和病理变化。体外对SG细胞进行有无PF以及有无ML385（Nrf2的特异性抑制剂）处理，然后用脂多糖（LPS）和三磷酸腺苷（ATP）诱导SG细胞中NLRP3炎性小体激活。结果NLRP3在SS患者的LG和SS小鼠的SG中上调。PF减轻了SS小鼠的干燥样症状。与对照组相比，PF组NOD小鼠SG中的NLRP3和半胱天冬酶-1以及血清IL-1β和IL-18降低。此外，我们发现PF通过激活SG细胞中的Nrf2/HO-1途径抑制NLRP3激活。此外，我们观察到PF给药后小鼠SG中Nrf2/HO-1的激活。
我们的研究结果表明，PF通过调节SS小鼠SG中的Nrf2/HO-1轴抑制NLRP3炎性小体激活，这可能是PF对SS治疗作用的潜在机制。
