Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction.
Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction.
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心肌细胞限制性表达 IL11 可导致心脏纤维化、炎症和功能障碍。
DOI：
10.3390/ijms241612989
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发表时间：
2023-08-20
影响因子：
5.6
通讯作者：
Cook, Stuart A.
中科院分区：
文献类型：
--
作者：
Sweeney, Mark;O'Fee, Katie;Villanueva-Hayes, Chelsie;Rahman, Ekhlas;Lee, Michael;Vanezis, Konstantinos;Andrew, Ivan;Lim, Wei-Wen;Widjaja, Anissa;Barton, Paul J. R.;Cook, Stuart A.
心脏纤维化是心脏疾病常见的病理过程，是治疗的靶点。转化生长因子β(转化生长因子β)是心脏纤维化的典型驱动力，最近发现其在成纤维细胞中的促纤维化作用依赖于白介素11(IL11)。相反，重组人IL11已被报道在小鼠心脏中具有抗纤维化和抗炎作用。在这项研究中，我们确定了IL11在心肌细胞中的表达对心脏病理生物学和功能的影响。我们使用Cre-loxP系统产生了他莫昔芬诱导的、心肌细胞受限的小鼠IL11表达。通过蛋白质分析、批量RNA测序和活体成像，我们分析了IL11对心肌纤维化、炎症和心功能的影响，挑战了先前关于IL11具有心脏保护潜力的报道。转化生长因子β刺激心肌细胞后，IL11表达上调。与野生型对照相比，表达IL11的心脏表现出严重的心脏纤维化和炎症，这与细胞因子、趋化因子、补体因子的上调和炎细胞的增加有关。IL11的表达还激活了内皮细胞向间充质细胞的转化程序，导致左心功能不全。我们的数据将物种匹配的IL11定义为从心肌细胞分泌时强烈的促纤维化和促炎作用，并进一步证实IL11是一种疾病因子。
Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor β (TGFβ) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFβ stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.
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影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1007/s12265-020-10054-z
发表时间：
2020-06-26
影响因子：
3.4
作者：
Corden, Ben;Lim, Wei-Wen;Cook, Stuart A.
通讯作者：
Cook, Stuart A.
影响因子：
3.1
作者：
Liu, Na-wei;Huang, Xin;Lu, Yue
通讯作者：
Lu, Yue
影响因子：
5.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Lim, Wei-Wen;Ng, Benjamin;Schafer, Sebastian
通讯作者：
Schafer, Sebastian