胃 Sonic Hedgehog 在对幽门螺杆菌的免疫反应中充当巨噬细胞趋化因子。
Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori.
机构信息
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0576, USA.
出版信息
Gastroenterology. 2012 May;142(5):1150-1159.e6. doi: 10.1053/j.gastro.2012.01.029. Epub 2012 Jan 25.
BACKGROUND & AIMS: Macrophages mediate the epithelial response to Helicobacter pylori and are involved in the development of gastritis. Sonic Hedgehog (Shh) regulates gastric epithelial differentiation and function, but little is known about its immunoregulatory role in the stomach. We investigated whether gastric Shh acts as a macrophage chemoattractant during the innate immune response to H pylori infection.
METHODS
Mice with parietal cell-specific deletion of Shh (PC-Shh(KO)) and control mice were infected with H pylori. Levels of gastric Shh, cytokines, and chemokines were assayed by quantitative reverse-transcriptase polymerase chain reaction or by a Luminex-based multiplex assay 2, 7, or 180 days after infection. Circulating concentrations of Shh were measured by enzyme-linked immunosorbent assay. Bone marrow chimera experiments were performed with mice that have myeloid cell-specific deletion of the Hedgehog signal transduction protein Smoothened (LysMCre/Smo(KO)). Macrophage recruitment was measured in gastric tissue and peripheral blood by fluorescence-activated cell sorting analysis.
RESULTS
Control mice infected with H pylori for 6 months developed an inflammatory response characterized by infiltration of CD4(+) T cells and increased levels of interferon gamma and interleukin 1β in the stomach. PC-Shh(KO) mice did not develop gastritis, even after 6 months of infection with H pylori. Control mice had increased concentrations of Shh, accompanied by the recruitment of CD11b(+)F4/80(+)Ly6C(high) macrophages 2 days after infection. Control mice that received bone marrow transplants from control mice had an influx of macrophages to the gastric mucosa in response to H pylori infection; this was not observed in H pylori-infected control mice that received bone marrow transplants from LysMCre/Smo(KO) mice.
CONCLUSIONS
H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.
背景与目的
巨噬细胞介导了幽门螺杆菌感染导致的上皮细胞反应，并参与了胃炎的发生。Sonic Hedgehog（Shh）调节胃上皮细胞的分化和功能，但对于其在胃中的免疫调节作用知之甚少。我们研究了胃 Shh 是否在幽门螺杆菌感染引发的固有免疫反应中作为巨噬细胞趋化因子发挥作用。
方法
用壁细胞特异性敲除 Shh（PC-Shh（KO））的小鼠和对照小鼠进行幽门螺杆菌感染。感染后 2、7 或 180 天，通过定量逆转录聚合酶链反应或基于 Luminex 的多重分析测定胃 Shh、细胞因子和趋化因子的水平。通过酶联免疫吸附试验测定循环 Shh 浓度。用骨髓特异性敲除 Hedgehog 信号转导蛋白 Smoothened（LysMCre/Smo（KO））的小鼠进行骨髓嵌合体实验。通过流式细胞术分析测定胃组织和外周血中的巨噬细胞募集情况。
结果
对照小鼠感染幽门螺杆菌 6 个月后，发展为炎症反应，其特征为胃内浸润的 CD4（+）T 细胞增加，以及干扰素 γ和白细胞介素 1β水平升高。即使感染幽门螺杆菌 6 个月，PC-Shh（KO）小鼠也未发生胃炎。对照小鼠在感染后 2 天 Shh 浓度增加，伴有 CD11b（+）F4/80（+）Ly6C（高）巨噬细胞募集。对照小鼠接受对照小鼠骨髓移植后，在感染幽门螺杆菌时会有大量巨噬细胞涌入胃黏膜；而在感染幽门螺杆菌的对照小鼠接受 LysMCre/Smo（KO）小鼠骨髓移植后，则观察不到这种情况。
结论
幽门螺杆菌诱导胃 Shh 释放；Shh 在胃炎起始时作为巨噬细胞趋化因子发挥作用。
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