Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Clin Sci (Lond). 2021 Feb 26;135(4):597-611. doi: 10.1042/CS20201438.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis.
We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model.
The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17.
Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.
溃疡性结肠炎（UC）是一种与免疫功能障碍相关的炎症性肠病（IBD）。最近的研究表明，神经分泌激素催产素（OXT）已被证明可缓解实验性结肠炎。
我们使用特定 OXTR 缺失的 CD11c+细胞（OXTRflox/flox×CD11c-cre 小鼠）和葡聚糖硫酸钠（DSS）诱导的结肠炎模型，研究了 OXT/OXT 受体（OXTR）信号在树突状细胞（DC）中的作用。
DSS 诱导的结肠炎小鼠的血清或结肠组织或 UC 患者的血浆中 OXT 水平异常。骨髓来源的 DC（BMDCs）和固有层 DC（LPDCs）均表达 OXTR。在 DC 中敲除 OXTR 可加重小鼠 DSS 诱导的急性和慢性结肠炎。相比之下，OXT 预处理的 DC 注射可显著改善结肠炎。在机制上，OXT 通过磷脂酰肌醇 4,5-二磷酸 3-激酶（Pi3K）/AKT 途径防止 DC 成熟，并促进 DC 的吞噬作用、黏附和细胞因子调节。此外，OXT 预处理的 DC 可防止 CD4+T 细胞向 Th1 和 Th17 分化。
我们的结果表明，OXT 诱导的耐受性 DC 通过 Pi3K/AKT 途径有效保护实验性结肠炎。我们的工作提供了证据，表明神经系统通过调节 DC 参与结肠炎的免疫调节。我们的发现表明，用 OXT 预处理体外产生的 DC 为人类 UC 的治疗开辟了新的治疗前景。
