Intestinal macrophages participate in the pathogenesis of inflammatory bowel diseases (IBDs) through secreting pro-inflammatory and tissue-damaging factors as well as inducing the differentiation of T helper 1 (Th1) and T helper 17 (Th17) cells. Elucidating the regulatory mechanisms of intestinal macrophage activity in IBDs is important for developing new therapeutic approaches. In the current study, the expression of Sestrins in myeloid cells and lymphocytes in colonic lamina propria (LP) was evaluated in a murine acute colitis model. We found that Sestrin3 was significantly up-regulated in LP macrophages by the colonic LP microenvironment. In the in vitro experiments, lentivirus-mediated Sestrin3 knockdown significantly reduced the production of IL-12 and IL-23 in activated macrophages, in addition to decreasing the expression of classical pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. Additionally, Sestrin3 knockdown impaired macrophage-mediated generation of Th1 and Th17 cells from CD4⁺ T cells, probably through up-regulating the phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) in macrophages. In the in vivo experiments, adoptive transfer of Sestrin3-deficient macrophages alleviated the generation of Th1 and Th17 cells in the colonic LP and mesenteric lymph nodes. Furthermore, the adoptive transfer mitigated the severity of colitis, as demonstrated by lower production of pro-inflammatory cytokines and fewer tissue lesions in the colon. Our study suggests that Sestrin3 might be crucial for macrophage-mediated generation of pathogenic Th1 and Th17 cells in IBDs.

中文翻译：

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Sestrin3 在小鼠结肠炎模型中增强巨噬细胞介导的 T 辅助 1 和 T 辅助 17 细胞的生成。

肠道巨噬细胞通过分泌促炎和组织损伤因子以及诱导 T 辅助 1 (Th1) 和 T 辅助 17 (Th17) 细胞的分化参与炎症性肠病 (IBD) 的发病机制。阐明 IBD 中肠道巨噬细胞活性的调节机制对于开发新的治疗方法很重要。在目前的研究中，在小鼠急性结肠炎模型中评估了结肠固有层 (LP) 中骨髓细胞和淋巴细胞中 Sestrins 的表达。我们发现结肠 LP 微环境在 LP 巨噬细胞中显着上调了 Sestrin3。在体外实验表明，慢病毒介导的 Sestrin3 敲低显着降低了活化巨噬细胞中 IL-12 和 IL-23 的产生，此外还降低了经典促炎细胞因子如 IL-1β、IL-6 和 TNF-α 的表达。此外，Sestrin3 敲低损害了巨噬细胞介导的从 CD4 ⁺ T 细胞生成 Th1 和 Th17 细胞，可能是通过上调巨噬细胞中雷帕霉素复合物 1 (mTORC1) 的机械靶标的磷酸化。在体内实验表明，过继转移 Sestrin3 缺陷型巨噬细胞减轻了结肠 LP 和肠系膜淋巴结中 Th1 和 Th17 细胞的产生。此外，过继转移减轻了结肠炎的严重程度，这表现为促炎细胞因子的产生减少和结肠组织损伤减少。我们的研究表明，Sestrin3 可能对 IBD 中巨噬细胞介导的致病性 Th1 和 Th17 细胞的产生至关重要。