Disruption of the intestinal barrier exacerbates experimental autoimmune pancreatitis by promoting the translocation of <i>Staphylococcus sciuri</i> into the pancreas
Disruption of the intestinal barrier exacerbates experimental autoimmune pancreatitis by promoting the translocation of <i>Staphylococcus sciuri</i> into the pancreas
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肠道屏障的破坏会促进<i>松鼠葡萄球菌</i>易位至胰腺，从而加剧实验性自身免疫性胰腺炎
DOI：
10.1093/intimm/dxac039
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发表时间：
2022
影响因子：
4.4
通讯作者：
Watanabe Tomohiro
中科院分区：
文献类型：
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作者：
Yoshikawa Tomoe;Minaga Kosuke;Hara Akane;Sekai Ikue;Kurimoto Masayuki;Masuta Yasuhiro;Otsuka Yasuo;Takada Ryutaro;Kamata Ken;Park Ah-Mee;Takamura Shiki;Kudo Masatoshi;Watanabe Tomohiro
肥胖是各种癌症的已知危险因素，它会减少肿瘤免疫微环境(TIME)中细胞毒性免疫细胞的数量和功能。然而，肥胖对CD4+T细胞的影响仍不清楚。因此，本研究旨在阐明肥胖对CD4+T细胞的影响时间。以45%高脂饲料(HFD)喂养小鼠，然后接种结肠癌细胞株MC38，建立荷瘤肥胖小鼠模型。与喂食对照饮食的小鼠相比，肿瘤的生长明显加快。肿瘤组织中CD_4~+T细胞数量明显减少，细胞程序性死亡-1(PD-1)表达增加，CD107a表达减少，细胞因子干扰素-γ和肿瘤坏死因子-α产生减少，提示功能障碍。我们进一步建立了CD4+T细胞耗竭的HFD喂养的小鼠模型，该模型显示肿瘤浸润减少，CD8+T细胞中PD-1表达增加，肥胖诱导的肿瘤生长加速，呈CD4+T细胞依赖的方式。这些发现表明，肥胖导致的CD4+T细胞数量减少和功能障碍导致了CD4+和CD8+T细胞抗肿瘤反应的降低，最终加速了结直肠癌的进展。我们的发现可能阐明结直肠癌与肥胖相关的不良预后的发病机制。
Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.