Epithelial Cell-Derived a Disintegrin and Metalloproteinase-17 Confers Resistance to Colonic Inflammation Through EGFR Activation.
Epithelial Cell-Derived a Disintegrin and Metalloproteinase-17 Confers Resistance to Colonic Inflammation Through EGFR Activation.
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DOI：
10.1016/j.ebiom.2016.02.007
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发表时间：
2016-03
期刊：
影响因子：
11.1
通讯作者：
Okada Y
中科院分区：
文献类型：
--
作者：
Shimoda M;Horiuchi K;Sasaki A;Tsukamoto T;Okabayashi K;Hasegawa H;Kitagawa Y;Okada Y
上皮再生是溃疡性结肠炎（UC）恢复的关键过程。在这里，我们证明了去整合素和金属蛋白酶-17（ADAM 17），一种肿瘤坏死因子（TNF）-α的主要脱落酶，通过促进上皮细胞生长和杯状细胞分化在小鼠和人中对UC的防御上皮特性是必不可少的。与骨髓细胞Adam 17缺失或对照同窝小鼠相比，Adam 17系统缺失的小鼠发生了严重的葡聚糖硫酸钠诱导的结肠炎。在对照小鼠中，ADAM 17主要由再生上皮表达，其缺失或抑制减弱了表皮生长因子受体（EGFR）活化、上皮增殖、粘液产生和屏障功能。相反，异位EGFR刺激促进上皮再生，从而部分挽救了ADAM 17缺陷引起的严重结肠炎。在UC患者中，上皮细胞ADAM 17表达与细胞增殖和杯状细胞数量呈正相关。这些发现表明，维持ADAM 17-EGFR上皮信号传导对于UC的恢复是必要的，并且将有利于靶向ADAM 17介导的TNF-α脱落的治疗策略。具有ADAM 17系统性缺失但不具有其骨髓细胞特异性缺陷的小鼠对结肠炎更敏感。ADAM 17-EGFR轴通过上皮细胞增殖和杯状细胞分化促进修复过程。溃疡性结肠炎患者上皮细胞ADAM 17表达与细胞生长和粘液产生相关。上皮再生是溃疡性结肠炎（UC）恢复的关键过程。我们现在证明，去整合素和金属蛋白酶-17（ADAM 17）是必不可少的防御上皮细胞的特性，对UC的驱动修复过程中，在小鼠和人类。在结肠炎症过程中，ADAM 17在再生上皮中上调，其缺失或抑制减弱表皮生长因子受体（EGFR）活化、上皮增殖、粘液产生和屏障功能。这些发现表明，维持ADAM 17-EGFR上皮信号传导对于UC的恢复是必要的，并且将有利于靶向ADAM 17介导的肿瘤坏死因子-α脱落的治疗策略。
Epithelial regeneration is a key process for the recovery from ulcerative colitis (UC). Here we demonstrate that a disintegrin and metalloproteinase-17 (ADAM17), a main sheddase for tumor necrosis factor (TNF)-α, is essential for defensive epithelial properties against UC by promoting epithelial cell growth and goblet cell differentiation in mouse and human. Mice with systemic deletion of Adam17 developed severe dextran sulfate sodium-induced colitis when compared to mice with myeloid cell Adam17 deletion or control littermates. ADAM17 was predominantly expressed by regenerating epithelia in control mice, and its loss or inhibition attenuated epidermal growth factor receptor (EGFR) activation, epithelial proliferation, mucus production and barrier functions. Conversely, ectopic EGFR stimulation promoted epithelial regeneration thereby partially rescuing the severe colitis caused by ADAM17 deficiency. In UC patients, epithelial ADAM17 expression positively correlated with both cell proliferation and goblet cell number. These findings suggest that maintaining ADAM17–EGFR epithelial signaling is necessary for the recovery from UC and would be beneficial to therapeutic strategies targeting ADAM17-mediated TNF-α shedding. Mice with systemic deletion of ADAM17, but not with its myeloid cell-specific deficiency, are more sensitive to colitis. ADAM17-EGFR axis promotes repair processes through epithelial cell proliferation and goblet cell differentiation. Epithelial ADAM17 expression correlates with cell growth and mucus production in ulcerative colitis patients. Epithelial regeneration is a key process for the recovery from ulcerative colitis (UC). We now demonstrate that a disintegrin and metalloproteinase-17 (ADAM17) is essential for defensive epithelial properties against UC by driving repair processes in mouse and human. During colonic inflammation, ADAM17 is up-regulated in regenerating epithelia, and its loss or inhibition attenuated epidermal growth factor receptor (EGFR) activation, epithelial proliferation, mucus production and barrier functions. These findings suggest that maintaining ADAM17–EGFR epithelial signaling is necessary for the recovery from UC and would be beneficial to therapeutic strategies targeting ADAM17-mediated tumor necrosis factor-α shedding.