腺苷 A2A 受体通过 γδ T 细胞——PKA/CREB/NF-κB 信号通路促进感染后肠易激综合征。
Adenosine 2A receptor contributes to the facilitation of post-infectious irritable bowel syndrome by γδ T cells the PKA/CREB/NF-κB signaling pathway.
机构信息
Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China.
Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90033, United States.
出版信息
World J Gastroenterol. 2023 Mar 7;29(9):1475-1491. doi: 10.3748/wjg.v29.i9.1475.
BACKGROUND
Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome (PI-IBS). γδ T cells play a crucial role in innate and adaptive immunity. Adenosine receptors expressed on the surface of γδ T cells participate in intestinal inflammation and immunity regulation.
AIM
To investigate the role of γδ T cell regulated by adenosine 2A receptor (A2AR) in PI-IBS.
METHODS
The PI-IBS mouse model has been established with infection. The intestinal A2AR and A2AR in γδ T cells were detected by immunohistochemistry, and the inflammatory cytokines were measured by western blot. The role of A2AR on the isolated γδ T cells, including proliferation, apoptosis, and cytokine production, were evaluated . Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction (RT-PCR). The animals were administered with A2AR agonist, or A2AR antagonist. Besides, γδ T cells were also injected back into the animals, and the parameters described above were examined, as well as the clinical features. Furthermore, the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.
RESULTS
PI-IBS mice exhibited elevated ATP content and A2AR expression ( < 0.05), and suppression of A2AR enhanced PI-IBS clinical characteristics, indicated by the abdominal withdrawal reflex and colon transportation test. PI-IBS was associated with an increase in intestinal T cells, and cytokine levels of interleukin-1 (IL-1), IL-6, IL-17A, and interferon-α (IFN-α). Also, γδ T cells expressed A2AR and generated IL-1, IL-6, IL-17A, and IFN-α, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that the A2AR antagonist improved the function of γδ T cells through the PKA/CREB/NF-κB signaling pathway.
CONCLUSION
Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function of γδ T cells the PKA/CREB/NF-κB signaling pathway.
背景
免疫功能障碍引起的低度炎症被认为是感染后肠易激综合征（PI-IBS）的主要发病机制之一。γδ T 细胞在先天和适应性免疫中发挥着关键作用。表达在 γδ T 细胞表面的腺苷受体参与肠道炎症和免疫调节。
目的
研究腺苷 2A 受体（A2AR）调节的 γδ T 细胞在 PI-IBS 中的作用。
方法
采用 感染建立 PI-IBS 小鼠模型。免疫组化检测肠道 A2AR 和 γδ T 细胞中的 A2AR，Western blot 检测炎症细胞因子。通过 Western blot 和逆转录聚合酶链反应（RT-PCR）检测分离的 γδ T 细胞增殖、凋亡和细胞因子产生等功能及其 A2AR 表达。动物给予 A2AR 激动剂或拮抗剂，回输 γδ T 细胞后观察上述参数及临床特征。进一步通过 Western blot 和 RT-PCR 检测 A2AR 相关信号通路分子。
结果
PI-IBS 小鼠表现出升高的 ATP 含量和 A2AR 表达（<0.05），抑制 A2AR 可增强 PI-IBS 临床特征，表现为腹壁退缩反射和结肠传输试验。PI-IBS 与肠道 T 细胞和细胞因子白细胞介素-1（IL-1）、IL-6、IL-17A 和干扰素-α（IFN-α）水平升高有关。此外，γδ T 细胞表达 A2AR 并产生 IL-1、IL-6、IL-17A 和 IFN-α，这些均可通过 A2AR 激动剂和拮抗剂控制。机制研究表明，A2AR 拮抗剂通过 PKA/CREB/NF-κB 信号通路改善 γδ T 细胞功能。
结论
我们的结果表明，A2AR 通过调节 γδ T 细胞功能促进 PI-IBS，其机制可能与 PKA/CREB/NF-κB 信号通路有关。
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