Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione
Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione
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DOI：
10.1053/j.gastro.2007.01.051
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发表时间：
2007-04-01
期刊：
影响因子：
29.4
通讯作者：
Sofroniew, Michael V.
中科院分区：
文献类型：
--
作者：
Savidge, Tor C.;Newman, Paul;Sofroniew, Michael V.
背景与目的：跨上皮和内皮的屏障功能对于稳态组织调节是必需的。星形胶质细胞与脑内皮细胞相互作用以维持血脑屏障。星形胶质细胞样肠神经胶质细胞和上皮细胞之间是否有类似的相互作用调节肠屏障功能尚不清楚。研究方法：在转基因小鼠中肠胶质细胞的条件性消融后，使用荧光通透性标记物来测量体内肠屏障功能。肠神经胶质细胞调节上皮屏障完整性，然后在体外使用共培养建模。胶质源性屏障诱导因子的特征在于使用尺寸排阻色谱和质谱。通过跨上皮阻力读数和通过定量聚合酶链反应和Western印迹定量测量紧密连接相关蛋白表达来评估上皮屏障完整性。结果：我们发现，在转基因小鼠肠神经胶质细胞的消融导致肠粘膜屏障功能障碍，导致炎症。胶质源性S-亚硝基谷胱甘肽（GSNO）被确定为体外和体内粘膜屏障功能的有效诱导剂，并在转基因小鼠肠胶质细胞消融后减弱组织炎症。GSNO对粘膜屏障功能的调节与连接周蛋白表达的增加直接相关。肌动蛋白和紧密连接相关蛋白质闭锁小带-1和occludin。GSNO还显著恢复了克罗恩病患者结肠活检标本的粘膜屏障功能，克罗恩病是一种与肠神经胶质细胞破坏相关的炎症性通透性障碍。结论：因此，肠神经胶质细胞具有星形胶质细胞调节紧密连接完整性的能力，并且与维持血脑屏障功能的细胞相互作用相当的细胞相互作用也调节粘膜表面的上皮通透性。
Background & Aims: Barrier functions across epithelia and endothelia are essential for homeostatic tissue regulation. Astroglia interact with cerebral endothelia to maintain the blood-brain barrier. Whether similar interactions between astrocyte-like enteric glia and epithelia regulate intestinal barrier function is not known. Methods: Fluorescent permeability markers were used to measure intestinal barrier function in vivo after conditional ablation of enteric glia in transgenic mice. Enteric glial cell regulation of epithelial barrier integrity then was modeled in vitro using coculture. Glial-derived barrier-inducing factors were characterized using size-exclusion chromatography and mass spectrometry. Epithelial barrier integrity was assessed by transepithelial resistance readings and by quantitative measurement of tight-junction-associated protein expression by quantitative polymerase chain reaction and Western blot. Results: We show that ablation of enteric glial cells in transgenic mice causes intestinal mucosal barrier dysfunction, resulting in inflammation. Glial-derived s-nitrosoglutathione (GSNO) was identified as a potent inducer of mucosal barrier function in vitro and in vivo and of attenuated tissue inflammation after ablation of enteric glia in transgenic mice. GSNO regulation of mucosal barrier function was associated directly with an increased expression of perijunctional. F-actin and tight-junction-associated proteins zonula occludens-1 and occludin. GSNO also significantly restored mucosal barrier function in colonic biopsy specimens from patients with Crohn's disease, a well-described inflammatory permeability disorder associated with enteric glial-cell disruption. Conclusions: Enteric glia therefore share the ability of astrocytes to regulate tight-junction integrity, and cellular interactions comparable with those maintaining blood-brain barrier function also regulate epithelial permeability at mucosal surfaces.