Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD.
Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD.
复制标题
DOI：
10.1097/mib.0000000000000384
复制
发表时间：
2015-06
影响因子：
4.9
通讯作者：
Siegmund B
中科院分区：
文献类型：
--
作者：
Lissner D;Schumann M;Batra A;Kredel LI;Kühl AA;Erben U;May C;Schulzke JD;Siegmund B
这篇文章于2015年4月21日首次在网上发表。补充数字内容可在正文中找到。巨噬细胞是炎症性肠病(IBD)的关键细胞。这项研究的目的是确定确定的巨噬细胞亚型对肠道上皮屏障完整性的部位特异性影响。采用免疫组织化学方法对IBD患者肠道组织中巨噬细胞亚型进行原位观察。人外周血CD14+细胞体外极化可产生M1或M2巨噬细胞。在原代人巨噬细胞与多层肠上皮细胞共培养模型中，通过跨上皮阻力测量、Western印迹分析、激光共聚焦扫描显微镜和流式细胞仪微珠阵列分析原代单核细胞或巨噬细胞亚型对上皮屏障完整性的影响。炎症性肠病患者的肠炎性固有层大量浸润，CD68+细胞也呈诱导型一氧化氮合酶和肿瘤坏死因子α阳性。M1巨噬细胞的存在使局部巨噬细胞间的平衡向促炎状态转变。在共培养模型中，单核细胞和M1巨噬细胞减少跨上皮阻力，作为上皮屏障完整性的标志。细胞旁渗漏的机制包括紧密连接蛋白Claudin-2在细胞内的重新定位和上皮细胞的凋亡。M_1巨噬细胞主要通过肿瘤坏死因子-α发挥毒害作用，而单核细胞介导的损伤主要由炎症体效应细胞因子、白介素1β和白介素18驱动。固有层单核细胞和M1巨噬细胞侵入肠道组织，通过解除紧密连接蛋白的调节，诱导上皮细胞凋亡，直接破坏上皮屏障，从而推动IBD的肠炎症。
Article first published online 21 April 2015. Supplemental Digital Content is Available in the Text. Macrophages are key players in inflammatory bowel diseases (IBD). This study aimed to determine site-specific effects of defined macrophage subtypes on the integrity of the intestinal epithelial barrier. Macrophage subtypes in situ in intestinal specimens of patients with IBD were visualized by immunohistochemistry. In vitro polarization of human peripheral CD14+ cells yielded M1 or M2 macrophages. The influence of primary monocytes or macrophage subtypes on epithelial barrier integrity was analyzed by transepithelial resistance measurements, Western blot analysis, confocal laser scanning microscopy, and cytometric bead array in a coculture model of primary human macrophages and layers of intestinal epithelial cell lines. The lamina propria of the inflamed intestine in patients with IBD, predominantly in Crohn's disease, is massively infiltrated by CD68+ cells also positive for inducible nitric oxide synthase and tumor necrosis factor (TNF) α. The presence of M1 macrophage shifted the balance in the local macrophage compartment towards a proinflammatory state. In the coculture model, monocytes and M1 macrophages reduced transepithelial resistance as a marker for epithelial barrier integrity. The mechanisms for paracellular leakage included intracellular relocalization of tight junction proteins like claudin-2 and epithelial cell apoptosis. Determined by specific cytokine blockade, M1 macrophages exerted their deleterious effect mainly through TNF-α, whereas monocyte-mediated damage was driven by the inflammasome effector cytokines, interleukin-1β and interleukin-18. Lamina propria monocytes and M1 macrophages invading intestinal tissues directly contribute to disrupting the epithelial barrier through deregulation of tight junction proteins and induction of epithelial cell apoptosis, thus driving intestinal inflammation in IBD.