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  • Title: [Mechanism of IL-17 Signaling Pathway in Spleen Inflammatory Response Induced by Altitude Hypoxia in Mice].
    Author: Yong S, Guo Y, Chen X, Xu Y, Hu Y.
    Journal: Sichuan Da Xue Xue Bao Yi Xue Ban; 2024 Jan 20; 55(1):118-124. PubMed ID: 38322537.
    Abstract:
    OBJECTIVE: To explore the mechanism of spleen tissue inflammatory response induced by altitude hypoxia in mice. METHODS: C57BL/6 mice were randomly assigned to a plain, i.e., low-altitude, normoxia group and an altitude hypoxia group, with 5 mice in each group. In the plain normoxia group, the mice were kept in a normoxic environment at the altitude of 400 m above sea level (with an oxygen concentration of 19.88%). The mice in the altitude hypoxia group were kept in an environment at the altitude of 4200 m above sea level (with an oxygen concentration of 14.23%) to establish the animal model of altitude hypoxia. On day 30, spleen tissues were collected to determine the splenic index. HE staining was performed to observe the histopathological changes in the spleen tissues of the mice. Real time fluorogenic quantitative PCR (RT-qPCR) and Western blot were conducted to determine the mRNA and protein expressions of interleukin (IL)-6, IL-12, and IL-1β in the spleen tissue of the mice. High-throughput transcriptome sequencing was performed with RNA sequencing (RNA-seq). KEGG enrichment analysis was performed for the differentially expressed genes (DEGs). The DEGs in the key pathways were verified by RT-qPCR. RESULTS: Compared with the plain normoxia group, the mice exposed to high-altitude hypoxic environment had decreased spleen index (P<0.05) and exhibited such pathological changes as decreased white pulp, enlarged germinal center, blurred edge, and venous congestion. The mRNA and protein expression levels of IL-6, IL-12, and IL-1β in the spleen tissue of mice in the altitude hypoxia group were up-regulated (P<0.05). According to the results of transcriptome sequencing and KEGG pathway enrichment analysis, 4218 DEGs were enriched in 178 enrichment pathways (P<0.05). DEGs were significantly enriched in multiple pathways associated with immunity and inflammation, such as T cell receptor signaling pathway, TNF signaling pathway, and IL-17 signaling pathway (P<0.05) in the spleen of mice exposed to high-altitude hypoxic environment. Among them, IL-17 signaling pathway and the downstream inflammatory factors were highly up-regulated (P<0.05). Compared with the plain normoxia group, the mRNA expression levels of key genes in the IL-17 signaling pathway, including IL-17, IL-17R, and mitogen-activated protein kinase genes (MAPKs), and the downstream inflammatory factors, including matrix metallopeptidase 9 (MMP9), S100 calcium binding protein A8 gene (S100A8), S100 calcium binding protein A9 gene (S100A9), and tumor necrosis factor α (TNF-α), were up-regulated or down-regulated (P<0.05) in the altitude hypoxia group. According to the validation of RT-qPCR results, the mRNA expression levels of DEGs were consistent with the RNA-seq results. CONCLUSION: Altitude hypoxia can induce inflammatory response in the mouse spleen tissue by activating IL-17 signaling pathway and promoting the release of downstream inflammatory factors. 目的: 探究高原低氧环境诱导小鼠脾脏组织炎症反应发生的作用机制。 方法: 将C57BL/6小鼠随机分为平原常氧组和高原低氧组，每组5只。其中，平原常氧组饲养于海拔400 m（氧浓度19.88%）常氧浓度环境，高原低氧组小鼠置于海拔4200 m（氧浓度14.23%）高原环境，构建高原低氧动物模型。第30天取脾脏组织检测脾脏指数，HE染色观察小鼠脾脏组织病理学改变，实时荧光定量PCR（RT-qPCR）和Western blot检测小鼠脾脏组织白细胞介素（IL）-6、IL-12、IL-1β的mRNA和蛋白表达量；使用RNA测序（RNA-sequencing, RNA-seq）技术进行高通量转录组学测序，将差异表达基因（differentially expressed genes, DEGs）进行KEGG富集分析，对关键通路中的DEGs进行RT-qPCR验证。 结果: 与平原常氧组相比，高原低氧环境下，小鼠脾脏指数降低（P<0.05），并出现白髓减少，生发中心扩大，边缘模糊，静脉充血等病理学改变；高原低氧组小鼠脾脏组织IL-6、IL-12、IL-1β的mRNA和蛋白表达量均上调（P<0.05）。经转录组测序，KEGG通路富集分析示，4218个DEGs共富集到178个富集通路（P<0.05），DEGs在T细胞受体信号通路、TNF信号通路和IL-17信号通路等多个与免疫、炎症相关通路中显著富集（P<0.05）；其中，IL-17信号通路和下游炎症因子高度上调表达（P<0.05）；与平原常氧组相比，高原低氧组小鼠脾脏组织IL-17信号通路中关键基因IL-17、IL-17R、MAPKs（mitogen-activated protein kinase genes）等和下游炎症因子MMP9（matrix metallopeptidase 9）、S100A8 （S100 calcium binding protein A8 gene）、S100A9 （S100 calcium binding protein A9 gene）、肿瘤坏死因子-α（tumour necrosis factor α, TNF-α）等基因的mRNA表达量均出现上调或下调差异表达（P<0.05）。经RT-qPCR验证，DEGs的mRNA表达量与RNA-seq结果一致。 结论: 高原低氧环境可通过激活IL-17信号通路，促进下游炎症因子释放，诱导小鼠脾脏组织炎症反应发生。
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