NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions.,Mucosal Immunology

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NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions.
Mucosal Immunology ( IF 8 ) Pub Date : 2019-Jan-01 , DOI: 10.1038/s41385-018-0086-4
Nesrine Makhezer _{1,

2} , Marwa Ben Khemis _{1,

2} , Dan Liu _{1,

2} , Yamina Khichane _{1,

2} , Viviana Marzaioli _{1,

2} , Asma Tlili _{1,

2} , Marjan Mojallali _{1,

2} , Coralie Pintard _{1,

2} , Philippe Letteron _{1,

2} , Margarita Hurtado-Nedelec _{1,

2,

3} , Jamel El-Benna _{1,

2} , Jean-Claude Marie _{1,

2} , Aurélie Sannier ₄ , Anne-Laure Pelletier ₅ , Pham My-Chan Dang _{1,

2}

Affiliation

Inflammatory bowel disease (IBD) is characterized by severe and recurrent inflammation of the gastrointestinal tract, associated with altered patterns of cytokine synthesis, excessive reactive oxygen species (ROS) production, and high levels of the innate immune protein, lipocalin-2 (LCN-2), in the mucosa. The major source of ROS in intestinal epithelial cells is the NADPH oxidase NOX1, which consists of the transmembrane proteins, NOX1 and p22^PHOX, and the cytosolic proteins, NOXO1, NOXA1, and Rac1. Here, we investigated whether NOX1 activation and ROS production induced by key inflammatory cytokines in IBD causally affects LCN-2 production in colonic epithelial cells. We found that the combination of TNFα and IL-17 induced a dramatic upregulation of NOXO1 expression that was dependent on the activation of p38MAPK and JNK1/2, and resulted into an increase of NOX1 activity and ROS production. NOX1-derived ROS drive the expression of LCN-2 by controlling the expression of IκBζ, a master inducer of LCN-2. Furthermore, LCN-2 production and colon damage were decreased in NOX1-deficient mice during TNBS-induced colitis. Finally, analyses of biopsies from patients with Crohn's disease showed increased JNK1/2 activation, and NOXO1 and LCN-2 expression. Therefore, NOX1 might play a key role in mucosal immunity and inflammation by controlling LCN-2 expression.

中文翻译：

NOX1 衍生的 ROS 在炎症条件下驱动结肠上皮细胞中 Lipocalin-2 的表达。

炎症性肠病 (IBD) 的特征是胃肠道严重和反复发炎，与细胞因子合成模式改变、活性氧 (ROS) 产生过多以及先天免疫蛋白脂质运载蛋白 2 (LCN- 2)、粘膜内。肠上皮细胞中 ROS 的主要来源是 NADPH 氧化酶 NOX1，它由跨膜蛋白、NOX1 和 p22 ^{PHOX 组成}和胞质蛋白 NOXO1、NOXA1 和 Rac1。在这里，我们研究了 IBD 中关键炎症细胞因子诱导的 NOX1 激活和 ROS 产生是否会影响结肠上皮细胞中 LCN-2 的产生。我们发现 TNFα 和 IL-17 的组合诱导依赖于 p38MAPK 和 JNK1/2 激活的 NOXO1 表达的显着上调，并导致 NOX1 活性和 ROS 产生的增加。NOX1 衍生的 ROS 通过控制 IκBζ（LCN-2 的主要诱导剂）的表达来驱动 LCN-2 的表达。此外，在 TNBS 诱导的结肠炎期间，NOX1 缺陷小鼠的 LCN-2 产生和结肠损伤减少。最后，对克罗恩病患者的活组织检查分析显示，JNK1/2 激活以及 NOXO1 和 LCN-2 表达增加。所以，

更新日期：2019-01-26

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