A disease-associated gene desert orchestrates macrophage inflammatory responses via ETS2
A disease-associated gene desert orchestrates macrophage inflammatory responses via ETS2
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DOI：
10.1101/2023.05.05.539522
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发表时间：
2023-05
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通讯作者：
C. Stankey;C. Bourges;T. Turner-Stokes;A. Piedade;C. Palmer-Jones;I. Papa;M. Dos Silva dos Santos;L. Randzavola;L. Speidel;E. Parkes;W. Edwards;A. Rochford;CD Murray;J. MacRae;P. Skoglund;C. Wallace;M. Cader;D. Thomas;Jcc Lee
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作者：
C. Stankey;C. Bourges;T. Turner-Stokes;A. Piedade;C. Palmer-Jones;I. Papa;M. Dos Silva dos Santos;L. Randzavola;L. Speidel;E. Parkes;W. Edwards;A. Rochford;CD Murray;J. MacRae;P. Skoglund;C. Wallace;M. Cader;D. Thomas;Jcc Lee
全球自身免疫性疾病和炎症性疾病发病率的上升对人类健康构成了迅速增长的威胁1。现有治疗方法的疗效有限1和药物开发过程中的高失败率2--突显了更好地了解疾病机制的迫切需要。在这里，我们展示了遗传学如何应对这一挑战。通过研究chr21q22上的一个基因间单倍型，与炎症性肠病(IBD)、强直性脊柱炎、原发性硬化性胆管炎和Takayasu的动脉炎3-6独立相关，我们发现原因基因ETS2是人类巨噬细胞炎症反应的主要调节基因，并描述了该风险单倍型如何增加ETS2的表达。受ETS2调控的基因在chr21q22相关疾病的受影响组织中显著表达，并且比几乎所有先前描述的途径更丰富地表达于IBD GWAITS。在静息巨噬细胞中过表达ETS2可产生激活效应状态，使IBD7的肠道巨噬细胞出现表型复制，并上调包括肿瘤坏死因子α和IL-23在内的多个药物靶点。利用细胞信号数据库，我们确定了可以调节这一途径的药物，并验证了一类小分子在体外和体外的有效抗炎活性。总而言之，这突显了共同基因关联改善对人类疾病的理解和治疗的潜力。
Increasing global rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2 – underscoring an urgent need to better understand disease mechanisms. Here we show how genetics could address this challenge. By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Genes regulated by ETS2 were prominently expressed in affected tissues from chr21q22-associated diseases and more enriched for IBD GWAS hits than almost all previously described pathways. Overexpressing ETS2 in resting macrophages produced an activated effector state that phenocopied intestinal macrophages from IBD7, with upregulation of multiple drug targets including TNFα and IL-23. Using a database of cellular signatures8, we identify drugs that could modulate this pathway and validate the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this highlights the potential for common genetic associations to improve both the understanding and treatment of human disease.