Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Gastroenterology. 2018 Sep;155(3):852-864.e3. doi: 10.1053/j.gastro.2018.05.033. Epub 2018 May 23.
BACKGROUND & AIMS: Psychological stress, in early life or adulthood, is a significant risk factor for inflammatory disorders, including inflammatory bowel diseases. However, little is known about the mechanisms by which emotional factors affect the immune system. γ-Aminobutyric acid type A receptors (GABARs) regulate stress and inflammation, but it is not clear whether specific subtypes of GABARs mediate stress-induced gastrointestinal inflammation. We investigated the roles of different GABAR subtypes in mouse colon inflammation induced by 2 different forms of psychological stress.
C57BL/6J mice were exposed to early-life stress, and adult mice were exposed to acute-restraint stress; control mice were not exposed to either form of stress. We collected colon tissues and measured contractility using isometric tension recordings; colon inflammation, based on levels of cluster of differentiation 163 and tumor necrosis factor messenger RNA (mRNA) and protein and myeloperoxidase activity; and permeability, based on levels of tight junction protein 1 and occludin mRNA and protein. Mice were given fluorescently labeled dextran orally and systemic absorption was measured. We also performed studies of mice with disruption of the GABAR subunit α3 gene (Gabra3 mice).
Mice exposed to early-life stress had significantly altered GABAR-mediated colonic contractility and impaired barrier function, and their colon tissue had increased levels of Gabra3 mRNA compared with control mice. Restraint stress led to colon inflammation in C57/BL6J mice but not Gabra3 mice. Colonic inflammation was induced in vitro by an α3-GABAR agonist, showing a proinflammatory role for this receptor subtype. In contrast, α1/4/5-GABAR ligands decreased the expression of colonic inflammatory markers.
We found stress to increase expression of Gabra3 and induce inflammation in mouse colon, together with impaired barrier function. The in vitro pharmacologic activation of α3-GABARs recapitulated colonic inflammation, whereas α1/4/5-GABAR ligands were anti-inflammatory. These proteins might serve as therapeutic targets for treatment of colon inflammation or inflammatory bowel diseases.
心理压力无论是在生命早期还是成年期，都是引发炎症性疾病（包括炎症性肠病）的重要危险因素。然而，情绪因素影响免疫系统的机制仍知之甚少。γ-氨基丁酸 A 型受体（GABARs）可调节应激和炎症，但尚不清楚 GABAR 特定亚型是否介导应激诱导的胃肠道炎症。我们研究了不同 GABAR 亚型在 2 种不同形式的心理应激诱导的小鼠结肠炎症中的作用。
将 C57BL/6J 小鼠暴露于早期生活应激中，将成年小鼠暴露于急性束缚应激中；对照组小鼠未暴露于任何形式的应激。我们采集结肠组织，使用等长张力记录测量收缩性；基于 CD163 和肿瘤坏死因子信使 RNA（mRNA）和蛋白以及髓过氧化物酶活性测量结肠炎症；基于紧密连接蛋白 1 和闭合蛋白 mRNA 和蛋白测量通透性。我们给小鼠口服荧光标记的葡聚糖，测量系统吸收情况。我们还进行了 GABAR 亚基 α3 基因缺失（Gabra3 小鼠）的研究。
暴露于早期生活应激的小鼠结肠的 GABAR 介导的收缩性发生明显改变，且屏障功能受损，与对照组小鼠相比，其结肠组织中 Gabra3 mRNA 水平增加。束缚应激导致 C57/BL6J 小鼠结肠炎症，但 Gabra3 小鼠未出现这种情况。α3-GABAR 激动剂在体外诱导结肠炎症，表明该受体亚型具有促炎作用。相反，α1/4/5-GABAR 配体降低了结肠炎症标志物的表达。
我们发现应激会增加 Gabra3 的表达，并诱导小鼠结肠炎症和屏障功能障碍。α3-GABAR 的体外药理学激活可重现结肠炎症，而α1/4/5-GABAR 配体具有抗炎作用。这些蛋白可能作为治疗结肠炎症或炎症性肠病的靶点。
