Pro-inflammatory cytokine TNFα antagonizes regulatory T cell (Treg) suppressive function with a measurable reduction of IL-10 protein secretion. Tregs are critical to suppress excessive immune activation, particularly within the intestine where high antigenic loads elicit chronic subclinical immune activation. Employing a TNFα-driven murine inflammatory bowel disease (IBD) model (TNF^ΔARE/+), which mirrors the Treg expansion and transmural ileitis seen in Crohn's disease, we demonstrate that the TNFα-mediated loss of Treg suppressive function coincides with induction of a specific miRNA, miR-106a in both humans and mice, via NFκB promoter binding to suppress post-transcriptional regulation of IL-10 release. Elevation of miR-106a and impaired Treg function in this model recapitulate clinical data from IBD patients. MiR-106a deficiency promotes Treg induction, suppressive function and IL-10 production in vitro. MiR-106a knockout attenuated chronic murine ileitis, whereas T cell restricted deficiency of miR-106a attenuated adoptive transfer colitis. In both models, attenuated inflammation coincided with suppression of both Th1 and Th17 cell subset expansion within the intestinal lamina propria. Collectively, our data demonstrate impaired Treg suppressive function in a murine IBD model consistent with human disease and support the potential for inhibition of miR-106a as a future therapeutic approach to treat chronic inflammatory conditions including IBD.

中文翻译：

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miR-106a 缺陷可减轻小鼠 IBD 模型中的炎症。

促炎细胞因子 TNFα 通过可测量的 IL-10 蛋白分泌减少来拮抗调节性 T 细胞 (Treg) 的抑制功能。Tregs 对于抑制过度免疫激活至关重要，特别是在肠道内，高抗原负荷会引发慢性亚临床免疫激活。采用 TNFα 驱动的小鼠炎症性肠病 (IBD) 模型 (TNF ^ΔARE/+)，这反映了在克罗恩病中观察到的 Treg 扩张和透壁性回肠炎，我们证明 TNFα 介导的 Treg 抑制功能丧失与特定 miRNA，miR-106a 在人类和小鼠中的诱导一致，通过 NFκB 启动子结合抑制IL-10 释放的转录后调控。该模型中 miR-106a 的升高和 Treg 功能受损概括了 IBD 患者的临床数据。MiR-106a 缺陷促进 Treg 诱导、抑制功能和 IL-10 的体外产生。MiR-106a 敲除减轻了慢性小鼠回肠炎，而 miR-106a 的 T 细胞限制性缺陷减轻了过继性转移性结肠炎。在这两种模型中，炎症减弱与肠固有层内 Th1 和 Th17 细胞亚群扩张的抑制同时发生。总的来说，