Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Immunol. 2022 Aug 12;13:863034. doi: 10.3389/fimmu.2022.863034. eCollection 2022.
Abnormal activation of the innate and adaptive immune systems has been observed in inflammatory bowel disease (IBD) patients. Anxiety and depression increase the risk of IBD by activating the adaptive immune system. However, whether anxiety affects innate immunity and its impact on IBD severity remains elusive. This study investigated the mechanism by which anxiety contributes to IBD development in a murine model of acute wrap restraint stress (WRS). Here, we found that anxiety-induced overactivation of group 2 innate lymphoid cells (ILC2) aggravated colonic inflammation. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of the physiological change of anxiety. Corticosterone (CORT), a stress hormone, is a marker of HPA axis activation and is mainly secreted by HPA activation. We hypothesized that the overproduction of CORT stimulated by anxiety exacerbated colonic inflammation due to the abnormally elevated function of ILC2. The results showed that ILC2 secreted more IL-5 and IL-13 in the WRS mice than in the control mice. Meanwhile, WRS mice experienced more body weight loss, shorter colon length, higher concentrations of IL-6 and TNF-α, more severely impaired barrier function, and more severe inflammatory cell infiltration. As expected, the serum corticosterone levels were elevated after restraint stress. Dexamethasone (DEX) was then injected to mimic HPA axis activation induced CORT secretion. DEX injection can also stimulate ILC2 to secrete more type II cytokines and exacerbate oxazolone (OXA) induced colitis. Blocking the IL-13/STAT6 signaling pathway alleviated colitis in WRS and DEX-injected mice. In conclusion, the overactivation of ILC2 induced by CORT contributed to the development of OXA-induced colitis in mice.
先天免疫系统和适应性免疫系统的异常激活在炎症性肠病（IBD）患者中观察到。焦虑和抑郁通过激活适应性免疫系统增加了 IBD 的风险。然而，焦虑是否影响先天免疫及其对 IBD 严重程度的影响仍不清楚。本研究在急性束缚应激（WRS）的小鼠模型中研究了焦虑导致 IBD 发展的机制。在这里，我们发现焦虑引起的 2 型固有淋巴细胞（ILC2）过度激活加重了结肠炎症。下丘脑-垂体-肾上腺（HPA）轴的过度激活是焦虑生理变化的标志。皮质酮（CORT），一种应激激素，是 HPA 轴激活的标志物，主要由 HPA 激活分泌。我们假设焦虑引起的 CORT 过度产生由于 ILC2 功能异常升高而加剧了结肠炎症。结果表明，WRS 小鼠的 ILC2 比对照小鼠分泌更多的 IL-5 和 IL-13。同时，WRS 小鼠经历了更多的体重减轻、更短的结肠长度、更高浓度的 IL-6 和 TNF-α、更严重的屏障功能受损和更严重的炎症细胞浸润。正如预期的那样，束缚应激后血清皮质酮水平升高。然后注射地塞米松（DEX）模拟 HPA 轴激活诱导的 CORT 分泌。DEX 注射也可以刺激 ILC2 分泌更多的 II 型细胞因子并加重氧化偶氮甲烷（OXA）诱导的结肠炎。阻断 IL-13/STAT6 信号通路可缓解 WRS 和 DEX 注射小鼠的结肠炎。总之，CORT 诱导的 ILC2 过度激活导致了 OXA 诱导的结肠炎在小鼠中的发展。
