Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [168 human cardiac fibroblasts]

Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs Overall design: 168 human cardiac fibroblasts. 84 control, 84 TGFB1 induced. Cardiac fibroblasts were cultured in serum-free media for at least 16 hours prior to treatment with TGFB1.

心脏纤维化是心脏病共通的终末期病理表现。本研究利用原代人心脏成纤维细胞（primary human heart fibroblasts）构建了整合成像-组学发现平台，旨在挖掘心脏纤维化的新型药物靶点。全基因组分析筛选出IL11——一种可被治疗性靶向抑制的分泌型细胞因子——作为最具潜力的促纤维化候选靶点。本研究证实IL11活性的自分泌环路是纤维化发生的关键环节，同时也是多种促纤维化刺激信号的汇聚枢纽。IL11可通过细胞外调节蛋白激酶（ERK）级联反应以顺式和反式方式传导信号，主要在蛋白质翻译层面激活纤维化相关程序。向小鼠体内注射IL11可诱导心脏、肾脏、肺脏、皮肤及肝脏发生纤维化，而敲除IL11受体的基因则可阻断多组织的纤维化进程。本研究数据揭示了一条全新的非经典纤维化通路，并将IL11确立为心脏及其他器官纤维化的新型治疗靶点。实验整体设计：168例人心脏成纤维细胞，分为84例对照组与84例转化生长因子β1（transforming growth factor β1，TGFB1）诱导组。实验前，心脏成纤维细胞于无血清培养基中培养至少16小时后再行TGFB1处理。