Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells
Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells
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DOI：
10.1053/j.gastro.2005.12.007
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发表时间：
2006-02-01
期刊：
影响因子：
29.4
通讯作者：
Mizoguchi, E
中科院分区：
文献类型：
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作者：
Mizoguchi, E
背景与目的：宿主/微生物相互作用失调似乎在炎症性肠病（IBD）的发展中起着核心作用。然而，导致clysregulation的分子事件尚未完全确定。研究旨在表征参与失调的关键分子。研究方法：对来自C57 BL/6小鼠在第4天和第8天给予4%葡聚糖硫酸钠5天的结肠粘膜RNA进行DNA微阵列分析。采用逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法检测CHi 3L 1 mRNA和蛋白表达。鼠伤寒沙门氏菌的庆大霉素保护试验使用经遗传工程改造以过表达或缺乏小鼠CHI 3L 1的上皮细胞系进行。为了检查CHI 3L 1在体内的功能作用，将抗CHI 31 -1抗体施用到葡聚糖硫酸钠结肠炎模型中。结果：微阵列分析表明，CHI 3L 1在炎症粘膜中特异性上调。CHI 3L 1蛋白的表达在几种小鼠结肠炎模型和溃疡性结肠炎和克罗恩病患者的固有层和结肠上皮细胞（CEC）中清楚地可检测到，但在正常对照中不存在。使用细胞内细菌的庆大霉素保护试验表明，CHI 3L 1是增强CEC中这些细菌的粘附和内化所必需的。体内中和实验表明，CHI 3L 1有助于促进细菌侵入肠粘膜和急性结肠炎的发展。结论：CHI 3L 1在结肠炎中起致病作用，可能是通过增强细菌在CEC上的粘附和侵袭。抑制CHI 3L 1活性将是IBD的一种新的治疗方法。
Background &Aims: Dysregulated host/microbial interactions appear to play a central role in the development of inflammatory bowel disease (IBD). However, molecular events leading to the clysregulation have not yet been defined fully. Studies were designed to characterize a key molecule that is involved in the dysregulation. Methods: Colonic mucosal RNA from C57BL/6 mice on days 4 and 8 with administration of 4% dextran sulfate sodium for 5 days were subjected to DNA microarray analysis. Chitinase 3-like-1 (CHi3L1) messenger RNA and protein expressions were examined by reverse-transcription polymerase chain reaction and immunohistochemistry. A gentamicin protection assay of Salmonella typhimurium was performed using epithelial cell lines that are engineered genetically to overexpress or lack mouse CHI3L1. To examine the functional role of CHI3L1 in vivo, anti-CHI31-1 antibody was administered into the dextran sulfate sodium colitis model. Results: Microarray analysis identified that CHI3L1 is up-regulated specifically in inflamed mucosa. The expression of CHI3L1 protein clearly was detectable in lamina propria and colonic epithelial cells (CECs) in several murine colitis models and ulcerative colitis and Crohn's disease patients but absent in normal controls. The gentamicin protection assays using intracellular bacteria showed that CHI3L1 is required for the enhancement of adhesion and internalization of these bacteria in CEC. In vivo neutralization experiments showed that CHI3L1 contributes to the facilitation of bacterial invasion into the intestinal mucosa and the development of acute colitis. Conclusions: CHI3L1 plays a pathogenic role in colitis, presumably by enhancing the adhesion and invasion of bacteria on/into CEC. Inhibition of CHI3L1 activity would be a novel therapeutic approach for IBD.