Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
J Neuroinflammation. 2022 Apr 4;19(1):73. doi: 10.1186/s12974-022-02431-z.
Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte-cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4β7 integrin, to initiate neuroimmune activation and anxiety-like behavior.
Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte-cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist.
The proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1β and CCL2 levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist.
In experimental colitis, α4β7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1β mediates anxiety-like behavior.
行为共病，如焦虑和抑郁，是 IBD 的一个突出特征。导致这些行为共病的肠道炎症信号在大脑中的变化仍有待充分阐明。我们假设在实验性结肠炎中，α4β7 整合素介导的白细胞-脑内皮细胞相互作用增强会发生在大脑中，从而引发神经免疫激活和焦虑样行为。
在急性结肠炎的高峰期，对用葡聚糖硫酸钠处理的雌性小鼠进行研究。使用流式细胞术测定循环白细胞群。用抗整合素抗体处理的小鼠，通过活体显微镜检查白细胞-脑内皮细胞相互作用。用动物用抗-α4β7 整合素治疗后的细胞因子和趋化因子的多指标测定评估脑内细胞因子和趋化因子。用脑室内注射白细胞介素 1 受体拮抗剂后，用高架十字迷宫评估焦虑样行为。
结肠炎小鼠外周血中表达 α4β7 整合素的经典单核细胞比例增加。观察到脑内皮细胞上滚动和黏附白细胞的数量增加，其中大多数是中性粒细胞。用抗-α4β7 整合素治疗可显著减少滚动白细胞的数量。在用抗 Ly6C 处理耗竭单核细胞后，结肠炎小鼠滚动和黏附中性粒细胞的数量显著减少。脑内白细胞介素-1β和 CCL2 水平升高，用抗-α4β7 治疗可显著降低其水平。用白细胞介素 1 受体拮抗剂治疗可逆转结肠炎小鼠的增强焦虑样行为。
在实验性结肠炎中，表达 α4β7 整合素的单核细胞指导中性粒细胞向脑血管的募集，导致细胞因子水平升高。白细胞介素-1β增加介导焦虑样行为。
