Yi Xiaoyan, Marmontel de Souza Bianca, Sawatani Toshiaki, Szymczak Florian, Marselli Lorella, Marchetti Piero, Cnop Miriam, Eizirik Decio L
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium.
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels 1050, Belgium.
iScience. 2022 Oct 17;25(11):105376. doi: 10.1016/j.isci.2022.105376. eCollection 2022 Nov 18.
Target tissues of autoimmune and degenerative diseases show signals of inflammation. We used publicly available RNA-seq data to study whether pancreatic β-cells in type 1 and type 2 diabetes and neuronal tissue in multiple sclerosis and Alzheimer's disease share inflammatory gene signatures. We observed concordantly upregulated genes in pairwise diseases, many of them related to signaling by interleukins and interferons. We next mined these signatures to identify therapies that could be re-purposed/shared among the diseases and identified the bromodomain inhibitors as potential perturbagens to revert the transcriptional signatures. We experimentally confirmed in human β-cells that bromodomain inhibitors I-BET151 and GSK046 prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1β and interferon-γ and at least some of the effects of the metabolic stressor palmitate. These results demonstrate that key inflammation-induced molecular mechanisms are shared between β-cells and brain in autoimmune and degenerative diseases and that these signatures can be mined for drug discovery.
自身免疫性疾病和退行性疾病的靶组织显示出炎症信号。我们利用公开可用的RNA测序数据，研究1型和2型糖尿病中的胰腺β细胞以及多发性硬化症和阿尔茨海默病中的神经元组织是否具有共同的炎症基因特征。我们观察到成对疾病中基因一致上调，其中许多基因与白细胞介素和干扰素信号传导有关。接下来，我们挖掘这些特征，以确定可在这些疾病中重新利用/共享的疗法，并确定溴结构域抑制剂是逆转转录特征的潜在干扰剂。我们在人β细胞中通过实验证实，溴结构域抑制剂I-BET151和GSK046可预防促炎细胞因子白细胞介素-1β和干扰素-γ的有害作用以及代谢应激源棕榈酸酯的至少部分作用。这些结果表明，在自身免疫性疾病和退行性疾病中，β细胞和大脑之间共享关键的炎症诱导分子机制，并且这些特征可用于药物发现。
