Yin Shaojie, Li Liuhui, Chen Xiaolan, Wang Jing, Mao Yujuan, Wang Jingxuan, Xie Xiaoyuting, Li Jingui, Yang Haifeng
Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China.
College of Applied Technology, Changzhou University, Changzhou, China.
Front Immunol. 2025 Feb 26;16:1545468. doi: 10.3389/fimmu.2025.1545468. eCollection 2025.
Innate and adaptive immunity are intricately linked to the pathogenesis of ulcerative colitis (UC), with dysregulation of the Treg/Th17 balance and M2/M1 macrophage polarization identified as critical factors. Artesunate (ARS) has previously been shown to alleviate UC by inhibiting endoplasmic reticulum stress (ERS). To further investigate the regulatory effects of ARS on immune dysregulation associated with colitis and the role of ERS in this process, an experimental colitis model was established using dextran sulfate sodium (DSS). Flow cytometry was employed to assess changes in the Th17/Treg cell ratio in the spleen and macrophage polarization in the intestine, while RT-qPCR was used to quantify the transcription levels of relevant genes in colonic tissues. ARS treatment significantly mitigated DSS-induced pathological damage, reduced the proportion of CD4Th17 cells, and downregulated the mRNA expression of IL-17A, IL-17F, and RORγt, while concurrently increasing the proportion of CD4Treg cells and upregulating TGF-β expression. Additionally, ARS restored the DSS-induced decline in the M2/M1 macrophage ratio and enhanced the transcription of Arg-1 and IL-10, while suppressing the expression of pro-inflammatory markers, including iNOS, IL-1β, IL-6, and TNF-α. Notably, co-treatment with 4-phenylbutyric acid (4-PBA, ERS inhibitor) augmented the immunoregulatory effects of ARS, whereas 2-deoxy-D-glucose (2-DG, ERS agonist) co-treatment counteracted its protective activity against UC. These findings suggest that ERS plays a crucial role in mediating the therapeutic effects of ARS on UC, particularly by modulating Th17/Treg balance and macrophage polarization. This study provides further insights into the mechanistic basis of ARS in UC treatment offering a potential avenue for therapeutic intervention.
固有免疫和适应性免疫与溃疡性结肠炎（UC）的发病机制密切相关，Treg/Th17平衡失调和M2/M1巨噬细胞极化被确定为关键因素。青蒿琥酯（ARS）先前已被证明可通过抑制内质网应激（ERS）来缓解UC。为了进一步研究ARS对与结肠炎相关的免疫失调的调节作用以及ERS在此过程中的作用，使用葡聚糖硫酸钠（DSS）建立了实验性结肠炎模型。采用流式细胞术评估脾脏中Th17/Treg细胞比例的变化以及肠道中巨噬细胞的极化情况，同时使用RT-qPCR定量结肠组织中相关基因的转录水平。ARS治疗显著减轻了DSS诱导的病理损伤，降低了CD4Th17细胞的比例，并下调了IL-17A、IL-17F和RORγt的mRNA表达，同时增加了CD4Treg细胞的比例并上调了TGF-β的表达。此外，ARS恢复了DSS诱导的M2/M1巨噬细胞比例下降，并增强了Arg-1和IL-10的转录，同时抑制了包括iNOS、IL-1β、IL-6和TNF-α在内的促炎标志物的表达。值得注意的是，与4-苯基丁酸（4-PBA，ERS抑制剂）联合治疗增强了ARS的免疫调节作用，而与2-脱氧-D-葡萄糖（2-DG，ERS激动剂）联合治疗则抵消了其对UC的保护活性。这些发现表明，ERS在介导ARS对UC的治疗作用中起着关键作用，特别是通过调节Th17/Treg平衡和巨噬细胞极化。本研究为ARS治疗UC的机制基础提供了进一步的见解，为治疗干预提供了一条潜在途径。
