Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.
Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.
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DOI：
10.1126/sciimmunol.abq6691
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发表时间：
2022-12-16
影响因子：
24.8
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫细胞是成纤维细胞产生细胞外基质（ECM）的基本调节因子，在炎症反应中决定纤维化程度方面发挥重要作用。尽管我们对纤维化中的成纤维细胞信号已经了解很多，但免疫细胞和成纤维细胞之间驱动其持续存在的分子信号却知之甚少。因此，我们分析了弥漫性皮肤系统性硬化症（一种导致皮肤和内脏纤维化的自身免疫性疾病）患者的皮肤和肺部样本。在这里，我们定义了树突状细胞和成纤维细胞之间的表调节蛋白- EGFR信号传导的关键作用，以维持纤维化组织中ECM的产生和积累。我们发现表调节蛋白的表达标志着I型干扰素触发DC3树突状细胞的诱导状态，并且DC3衍生的表调节蛋白激活成纤维细胞上的EGFR，通过NOTCH信号驱动一个正反馈循环。在小鼠皮肤和肺纤维化模型中，表调节蛋白对于两种组织中纤维化的持续存在至关重要，这可以通过表调节蛋白基因缺乏或中和抗体来消除。值得注意的是，表调节蛋白抗体的治疗性管理逆转了患者皮肤和肺移植的纤维化，将其确定为以前未开发的生物药物靶点。我们的研究结果表明，表调节蛋白是一种重要的免疫信号，在多种疾病中维持皮肤和肺纤维化，是一种有希望的抗纤维化靶点。表调节蛋白是一种由DC3树突状细胞产生的EGFR配体，对皮肤和肺纤维化的持续存在至关重要。
Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here, we define a critical role of epiregulin – EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Notably, therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target. Epiregulin is an EGFR ligand produced by DC3 dendritic cells that is essential for persistence of skin and lung fibrosis.
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影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
DOI：
10.1073/pnas.0700021104
发表时间：
2007-02-20
影响因子：
11.1
作者：
Aliprantis, Antonios O.;Wang, Jingsong;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
27.4
作者：
Eloranta, Maija-Leena;Franck-Larsson, Karin;Ronnblom, Lars
通讯作者：
Ronnblom, Lars
影响因子：
4.8
作者：
Bublil, Erez M.;Pines, Gur;Yarden, Yosef
通讯作者：
Yarden, Yosef
影响因子：
2.2
作者：
Chua, Siang Ling;Too, Wei Cun See;Few, Ling Ling
通讯作者：
Few, Ling Ling