Li Ning, Xu Tianhao, Wu Zhaoshun, Zhao Yuchen, Ruan Ming, Xu Hao, Chen Weihao, Wang Huijun, Wang Shunchun, Wang Yongjun, Liang Qianqian
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai 200032, PR China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai 200032, PR China.
The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China.
Phytomedicine. 2025 Jan;136:156269. doi: 10.1016/j.phymed.2024.156269. Epub 2024 Nov 19.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by multiple joints lesions. Tolerogenic dendritic cells (tolDCs) play crucial roles in maintaining immune homeostasis. The immunomodulatory activity of plant-derived arabinogalactan (AGs) has been well investigated, however, whether AGs could suppress autoimmune responses by inducing tolDCs is remain unclear.
Collagen-induced arthritis (CIA, a mouse model of RA) mice were utilized to ascertain the role of AGs (obtained from Cynanchum atratum) in autoimmune responses. An antibiotic cocktail was administered to eliminate gut microbiota. Germ-free (GF) and Toll-like receptor 2 (TLR2) knockout mice were used to determine the function of AGs in intestinal immune cells.
The oral administration of dietary AGs substantially reduced the severity of CIA and rebalanced the ratio of regulatory T cells (Tregs) to T helper 17 (Th17) cells. Although the antibiotic cocktail depleted the mice's gut microbiota, AGs had a therapeutic effect on their CIA. AGs restored Treg/Th17 homeostasis by inducing CD103 tolDCs, regardless of the gut microbiota of the GF mice. Coculture experiments confirmed that AGs induced tolDCs and transforming growth factor β (TGF-β) secretion, leading to Treg amplification. RNA sequencing and TLR2 knockout experiments revealed that AGs induced tolDCs through a TLR2-mediated mechanism. Preventive interventions with AGs established a tolerogenic intestinal immune microenvironment, which delayed the onset and progression of CIA. AGs functioned synergistically with tofacitinib, a JAK inhibitor, to effectively restore Treg/Th17 balance and alleviate CIA.
This study introduces a novel microbiota-independent mechanism through which soluble dietary AGs inhibit systemic autoimmune responses. Our findings provide insights into the supplementation of dietary AGs in patients with preclinical or progressive RA.
类风湿性关节炎（RA）是一种以多关节病变为特征的自身免疫性疾病。耐受性树突状细胞（tolDCs）在维持免疫稳态中起关键作用。植物来源的阿拉伯半乳聚糖（AGs）的免疫调节活性已得到充分研究，然而，AGs是否能通过诱导tolDCs来抑制自身免疫反应仍不清楚。
利用胶原诱导性关节炎（CIA，一种RA小鼠模型）小鼠来确定AGs（从白薇中获得）在自身免疫反应中的作用。给予抗生素混合物以消除肠道微生物群。使用无菌（GF）和Toll样受体2（TLR2）基因敲除小鼠来确定AGs在肠道免疫细胞中的功能。
口服膳食AGs可显著降低CIA的严重程度，并重新平衡调节性T细胞（Tregs）与辅助性T细胞17（Th17）的比例。尽管抗生素混合物耗尽了小鼠的肠道微生物群，但AGs对其CIA仍有治疗作用。无论GF小鼠的肠道微生物群如何，AGs通过诱导CD103 tolDCs恢复Treg/Th17稳态。共培养实验证实，AGs诱导tolDCs和转化生长因子β（TGF-β）分泌，导致Treg扩增。RNA测序和TLR2基因敲除实验表明，AGs通过TLR2介导的机制诱导tolDCs。AGs的预防性干预建立了一种耐受性肠道免疫微环境，延缓了CIA的发病和进展。AGs与JAK抑制剂托法替布协同作用，有效恢复Treg/Th17平衡并减轻CIA。
本研究引入了一种新的不依赖微生物群系的机制，通过该机制可溶性膳食AGs可抑制全身性自身免疫反应。我们的研究结果为临床前或进展性RA患者补充膳食AGs提供了见解。
