A marked egg-induced CD4+ T cell programmed inflammation and subsequent hepatic fibrosis characterize the pathogenesis of schistosomiasis. Mesenchymal stem cell (MSC) has been extensively studied for the treatment of schistosomiasis. However, the mechanism by which MSCs modulate the pathogenesis of schistosomiasis has not been clarified. Furthermore, the local inflammatory milieu may greatly influence the immunoregulatory properties of MSCs, and our early experiments demonstrated that Toll-like receptor (TLR)2/TLR4 agonist effected immune modulation of MSC. Here, we further investigated their modulation on the pathogenesis of schistosomiasis. Adult BALB/c male mice were percutaneously infected with 16 ± 2 pairs S. japonicum cercariae and received intravenously pretreated MSC at 1 week and 3 weeks post-infection, respectively. At 8 weeks post-infection, effects of MSC on liver histology were shown by hematoxylin and eosin (H&E) staining and Masson staining and quantitatively compared by the hepatic hydroxyproline content; α-smooth muscle actin (α-SMA), collagen type I(Col-1), transforming growth factor β (TGF-β), and tumor necrosis factor-α (TNF-α) gene expression in the liver were assessed by semi-quantitative polymerase chain reaction (PCR); the Th1/Th2 dominance among different groups was compared by analyzing CD4+ interferon-γ (IFN-γ)+ and CD4+interleukin-4 (IL-4)+T cells in the liver by flow cytometry and serum level of IFN-γ and IL-5 using enzyme-linked immunosorbent assay (ELISA). Effects of different kinds of MSC were further evaluated in vitro by the coculture system. Results showed TLR4- and IFN-γ-activated MSC alleviated liver fibrosis in infected mice, without a significant increase of mortality, and unpretreated MSC showed no clear improvement; however, TLR2- and IFN-γ-activated MSC displayed aggravated immunopathology. In accord with the pathological results, TLR4- and IFN-γ-activated MSC groups showed moderate enhancement of Th1 response in vitro and clear Th1 dominance in vivo without leading to extreme inflammation, whereas TLR2- and IFN-γ-activated MSC not only induced Th1 response, but also triggered excessive inflammation as evidenced by atrophy of the thymus and higher TNF level in the coculture system. This study demonstrates that TLR4 combined with IFN-γ can activate the MSC group with positive effects on the pathology of schistosomiasis by modulating Th subsets at some degree. This result suggests that when MSC is being used to treat different immuno-disturbance complications, subtle pretreatment methods should be seriously considered.

中文翻译：

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血吸虫病的免疫病理学受 TLR2,4 和 IFN-γ 激活的 MSC 通过调节 Th1/Th2 反应的调节。

明显的鸡蛋诱导的 CD4+ T 细胞程序性炎症和随后的肝纤维化是血吸虫病发病机制的特征。间充质干细胞 (MSC) 已被广泛研究用于治疗血吸虫病。然而，MSCs调节血吸虫病发病机制的机制尚未阐明。此外，局部炎症环境可能极大地影响 MSCs 的免疫调节特性，我们的早期实验表明 Toll 样受体 (TLR)2/TLR4 激动剂影响 MSCs 的免疫调节。在这里，我们进一步研究了它们对血吸虫病发病机制的调节作用。成年 BALB/c 雄性小鼠分别在感染后 1 周和 3 周用 16 ± 2 对日本血吸虫尾蚴经皮感染并接受静脉预处理的 MSC。感染后8周，通过苏木精和伊红（H&E）染色和Masson染色显示MSC对肝脏组织学的影响，并通过肝脏羟脯氨酸含量进行定量比较；α-平滑肌肌动蛋白 (α-SMA)、I 型胶原蛋白 (Col-1)、转化生长因子 β (TGF-β) 和肿瘤坏死因子-α (TNF-α) 基因在肝脏中的表达通过半-定量聚合酶链反应（PCR）；通过流式细胞仪分析肝脏中CD4+干扰素-γ（IFN-γ）+和CD4+白细胞介素4（IL-4）+T细胞及血清IFN-γ水平，比较不同组间Th1/Th2优势。 IL-5采用酶联免疫吸附试验（ELISA）。通过共培养系统在体外进一步评估了不同种类MSC的作用。结果显示 TLR4 和 IFN-γ 激活的 MSC 减轻了感染小鼠的肝纤维化，死亡率没有显着增加，未经预处理的 MSC 没有明显改善；然而，TLR2 和 IFN-γ 激活的 MSC 表现出加重的免疫病理学。与病理结果一致，TLR4 和 IFN-γ 激活的 MSC 组在体外显示 Th1 反应适度增强，在体内明显 Th1 优势，而不会导致极度炎症，而 TLR2 和 IFN-γ 激活的 MSC 不仅诱导Th1 反应，但也引发了过度炎症，如共培养系统中胸腺萎缩和更高 TNF 水平所证明的那样。本研究表明，TLR4联合IFN-γ可在一定程度上通过调节Th亚群激活MSC组，对血吸虫病病理产生积极影响。这一结果表明，当使用 MSC 治疗不同的免疫紊乱并发症时，