Yazar Volkan, Yilmaz Ismail Cem, Bulbul Artun, Klinman Dennis M, Gursel Ihsan
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Thorlab, Molecular Biology and Genetics Department, Faculty of Science, Ihsan Dogramaci Bilkent University, 06800 Ankara, Turkey.
Mol Ther Nucleic Acids. 2023 Feb 4;31:553-565. doi: 10.1016/j.omtn.2023.02.004. eCollection 2023 Mar 14.
Homeostatic restoration of an inflammatory response requires quenching of the immune system after pathogen threats vanish. A continued assault orchestrated by host defense results in tissue destruction or autoimmunity. A151 is the epitome of synthetic oligodeoxynucleotides (ODNs) that curb the immune response by a subset of white corpuscles through repetitive telomere-derived TTAGGG sequences. Currently, the genuine effect of A151 on the immune cell transcriptome remains unknown. Here, we leveraged an integrative approach where weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, and gene set enrichment analysis (GSEA) of our in-house microarray datasets aided our understanding of how A151 ODN suppresses the immune response in mouse splenocytes. Our bioinformatics results, together with experimental validations, indicated that A151 ODN acts on components of integrin complexes, and , to interfere with immune cell adhesion and thereby suppresses the immune response in mice. Moreover, independent lines of evidence in this work converged on the observation that cell adhesion by integrin complexes serves as a focal point for cellular response to A151 ODN treatment in immune cells. Taken together, the outcome of this study sheds light on the molecular basis of immune suppression by a clinically useful DNA-based therapeutic agent.
炎症反应的稳态恢复需要在病原体威胁消失后使免疫系统失活。宿主防御系统持续发动攻击会导致组织破坏或自身免疫。A151是合成寡脱氧核苷酸（ODN）的典型代表，它通过重复的端粒衍生TTAGGG序列抑制一部分白细胞的免疫反应。目前，A151对免疫细胞转录组的真正作用尚不清楚。在这里，我们采用了一种综合方法，即对我们内部的微阵列数据集进行加权基因共表达网络分析（WGCNA）、差异基因表达分析和基因集富集分析（GSEA），以帮助我们了解A151 ODN如何抑制小鼠脾细胞中的免疫反应。我们的生物信息学结果以及实验验证表明，A151 ODN作用于整合素复合物的成分，以及，以干扰免疫细胞粘附，从而抑制小鼠的免疫反应。此外，这项工作中的独立证据线索都集中在一个观察结果上，即整合素复合物介导的细胞粘附是免疫细胞对A151 ODN治疗产生细胞反应的焦点。综上所述，这项研究的结果揭示了一种临床上有用的基于DNA的治疗剂免疫抑制的分子基础。
