IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica.
IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica.
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IL-33/ST2 轴缺陷通过调节日本血吸虫病中的 Treg 和 Th17 细胞加剧肝脏病理学
DOI：
10.2147/jir.s336404
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发表时间：
2021
影响因子：
4.5
通讯作者：
Lei J
中科院分区：
文献类型：
--
作者：
Bai Y;Guan F;Zhu F;Jiang C;Xu X;Zheng F;Liu W;Lei J
利用日本血吸虫感染的IL-33和ST2基因缺陷（分别为IL-33−/−和ST2−/−）小鼠，探讨IL-33/ST2轴在靶向调节性T细胞(Treg)/T辅助17细胞（Th17）的肝脏病理中的作用。每只小鼠经皮感染20只日本血吸虫尾蚴。检测肝质量指数（HMI）、肝卵肉芽肿、肝纤维化生物标志物及血清丙氨酸转氨酶（ALT）水平。流式细胞术检测Treg和Th17频率。采用实时荧光定量聚合酶链式反应（qRT-PCR）检测Foxp3、ST2、TGF-β1、IL-10、rorr γt、IL-17A的表达。ELISA法检测TGF-β1、IL-10、IL-17A的浓度。体外实验采用qRT-PCR检测重组小鼠IL-33 （rmIL-33）诱导Treg极化相关的Foxp3、TGF-β1、IL-10、Atg5、Beclin-1和p62 mRNA表达。IL-33/ST2在日本血吸虫感染小鼠中表达升高。IL-33或ST2基因缺失导致肝脏病理加重，表现为肝肉芽肿体积、HMI和ALT水平升高，纤维化表现为感染小鼠肝胶原沉积增加。向感染的IL-33 - / -小鼠注射rmIL-33可明显消除肝脏病理和纤维化，而向感染的ST2 - / -小鼠注射rmIL-33则无明显作用。此外，IL-33/ST2轴的缺失抑制Treg，并伴有Th17的增加。在感染IL-33−/−小鼠中，rmIL-33处理上调Treg，下调Th17，而在感染ST2−/−小鼠中无影响。rmIL-33导致Atg5、Beclin-1的表达升高，抑制p62在Treg扩增中的表达。IL-33/ST2轴在日本血吸虫感染小鼠中发挥保护作用，其作用机制与增加Treg应答和抑制Th17应答密切相关。IL-33对Treg的扩增可能与其调控自噬有关。
Schistosoma japonicum-infected IL-33 and ST2 gene deficiency (IL-33−/− and ST2−/−, respectively) mice were used to explore the role of the IL-33/ST2 axis in liver pathology targeting regulatory T cells (Treg)/T helper 17 cells (Th17). Each mouse was infected percutaneously with 20 S. japonicum cercariae. Hepatic mass index (HMI), liver egg granulomas, hepatic fibrosis biomarkers and serum levels of alanine aminotransferase (ALT) were investigated. Treg and Th17 frequency was determined by flow cytometry. Expressions of Foxp3, ST2, TGF-β1, IL-10, RORγt, and IL-17A were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Concentrations of TGF-β1, IL-10 and IL-17A were tested with ELISA. In vitro experiments, mRNA expressions of Foxp3, TGF-β1, IL-10, Atg5, Beclin-1 and p62 associated with polarization of Treg by recombinant mouse IL-33 (rmIL-33) were detected by qRT-PCR. An increased expression of IL-33/ST2 was shown in S. japonicum-infected mice. Deficiency of IL-33 or ST2 gene led to an aggravated liver pathology, which was evidenced by elevated hepatic granuloma volume, HMI and ALT levels and fibrosis, which was demonstrated by increased hepatic collagen deposition in the infected mice. Injection of rmIL-33 into the infected IL-33−/− mice strongly abrogated the liver pathology and fibrosis, whereas no detectable effect with injecting rmIL-33 into the infected ST2−/− mice. Furthermore, depletion of the IL-33/ST2 axis inhibited Treg, accompanied by increased Th17. rmIL-33 treatment upregulated Treg and downregulated Th17 in the infected IL-33−/− mice, while no effect in the infected ST2−/− mice. rmIL-33 led to elevated expressions of Atg5, Beclin-1 and inhibited expression of p62 in expansion of Treg. The IL-33/ST2 axis plays a protective role in S. japonicum infected mice, which is closely related to increasing Treg responses as well as suppressing Th17 responses. Expansion of Treg by IL-33 may be associated with its regulation of autophagy.