Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, 7780272, Ñuñoa, Santiago, Chile.
Universidad San Sebastián, 7510156, Providencia, Santiago, Chile.
Mucosal Immunol. 2021 May;14(3):652-666. doi: 10.1038/s41385-020-00354-7. Epub 2020 Nov 12.
Evidence from inflammatory bowel diseases (IBD) patients and animal models has indicated that gut inflammation is driven by effector CD4 T-cell, including Th1 and Th17. Conversely, Treg seem to be dysfunctional in IBD. Importantly, dopamine, which is abundant in the gut mucosa under homoeostasis, undergoes a sharp reduction upon intestinal inflammation. Here we analysed the role of the high-affinity dopamine receptor D3 (DRD3) in gut inflammation. Our results show that Drd3 deficiency confers a stronger immunosuppressive potency to Treg, attenuating inflammatory colitis manifestation in mice. Mechanistic analyses indicated that DRD3-signalling attenuates IL-10 production and limits the acquisition of gut-tropism. Accordingly, the ex vivo transduction of wild-type Treg with a siRNA for Drd3 induced a potent therapeutic effect abolishing gut inflammation. Thus, our findings show DRD3-signalling as a major regulator of Treg upon gut inflammation.
炎症性肠病（IBD）患者和动物模型的证据表明，肠道炎症是由效应性 CD4 T 细胞驱动的，包括 Th1 和 Th17。相反，Treg 在 IBD 中似乎功能失调。重要的是，多巴胺在肠道炎症发生时在肠道黏膜中大量减少。在这里，我们分析了高亲和力多巴胺受体 D3（DRD3）在肠道炎症中的作用。我们的结果表明，Drd3 缺乏赋予 Treg 更强的免疫抑制能力，从而减轻小鼠的炎症性结肠炎表现。机制分析表明，DRD3 信号减弱了 IL-10 的产生，并限制了肠道归巢的获得。因此，用 Drd3 的 siRNA 对野生型 Treg 进行体外转导可引起有效的治疗效果，从而消除肠道炎症。因此，我们的研究结果表明，DRD3 信号在肠道炎症时是 Treg 的主要调节因子。
