Epithelial p38alpha controls immune cell recruitment in the colonic mucosa.
Epithelial p38alpha controls immune cell recruitment in the colonic mucosa.
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DOI：
10.1371/journal.ppat.1000934
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发表时间：
2010-06-03
期刊：
影响因子：
6.7
通讯作者：
Han J
中科院分区：
文献类型：
--
作者：
Kang YJ;Otsuka M;van den Berg A;Hong L;Huang Z;Wu X;Zhang DW;Vallance BA;Tobias PS;Han J
肠上皮细胞（IEC）构成胃肠道中抵抗微生物的第一道屏障。尽管最近证明 IEC 中的 NF-κB 通路对于上皮完整性和肠道免疫稳态至关重要，但其他炎症信号通路在 IEC 免疫反应中的作用仍然很大程度上未知。在这里，我们表明 IEC 中的 p38α 对于趋化因子的表达、随后的免疫细胞招募到肠粘膜以及清除受感染的病原体至关重要。 IEC 中 p38α 缺失的小鼠在接种啮齿类柠檬酸杆菌后会遭受持续的细菌负担。这些动物的上皮完整性和免疫细胞功能正常，但无法将 CD4+ T 细胞募集到结肠粘膜病变中。 IEC 中趋化因子的表达受损，这似乎是 T 细胞募集受损的原因。因此，IEC 中的 p38α 通过招募免疫细胞来促进宿主针对肠道细菌的免疫反应。肠上皮细胞（IEC）对胃肠道微生物的细胞反应是通过许多细胞内信号通路的激活介导的。结果表明，IEC 中的 NF-κB 通路对于上皮完整性和肠道免疫稳态至关重要，在这里我们表明 IEC 中 p38α 介导的信号对上皮完整性和免疫细胞功能并不重要，但对于清除感染病原体至关重要。 IEC 中的 p38α 对于 IEC 中病原体诱导的趋化因子表达以及随后的免疫细胞募集到肠粘膜中至关重要，从而导致感染性病原体的清除。我们的结果表明，IEC 中不同的细胞内信号通路介导对胃肠道微生物的不同细胞反应，在开发针对胃肠道感染的通路靶向治疗干预措施时应考虑这一信息。
Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-κB pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38α in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38α deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4+ T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38α in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells. The cellular responses of intestinal epithelial cells (IECs) to microorganisms in the gastrointestinal tract are mediated by activation of a number of intracellular signaling pathways. It was shown that the NF-κB pathway in IECs is essential for epithelial integrity and intestinal immune homeostasis, and here we show that p38α-mediated signaling in IECs is not important for epithelial integrity and immune cell function, but is critical for the clearance of the infected pathogen. p38α in IECs is essential for pathogen-induced chemokine expression in IECs and for subsequent immune cell recruitment into the intestinal mucosa, which leads to the clearance of the infectious pathogen. Our results indicate that different intracellular signaling pathways in IECs mediate distinct cellular responses to microorganisms in the gastrointestinal tract, and this information should be taken into consideration in the development of pathway-targeted therapeutic interventions for gastrointestinal infection.
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