Earlham Institute, Norwich NR4 7UZ, UK.
Quadram Institute Bioscience, Norwich NR4 7UZ, UK.
Cells. 2021 Aug 29;10(9):2242. doi: 10.3390/cells10092242.
Intercellular communication mediated by cytokines is critical to the development of immune responses, particularly in the context of infectious and inflammatory diseases. By releasing these small molecular weight peptides, the source cells can influence numerous intracellular processes in the target cells, including the secretion of other cytokines downstream. However, there are no readily available bioinformatic resources that can model cytokine-cytokine interactions. In this effort, we built a communication map between major tissues and blood cells that reveals how cytokine-mediated intercellular networks form during homeostatic conditions. We collated the most prevalent cytokines from the literature and assigned the proteins and their corresponding receptors to source tissue and blood cell types based on enriched consensus RNA-Seq data from the Human Protein Atlas database. To assign more confidence to the interactions, we integrated the literature information on cell-cytokine interactions from two systems of immunology databases, immuneXpresso and ImmunoGlobe. From the collated information, we defined two metanetworks: a cell-cell communication network connected by cytokines; and a cytokine-cytokine interaction network depicting the potential ways in which cytokines can affect the activity of each other. Using expression data from disease states, we then applied this resource to reveal perturbations in cytokine-mediated intercellular signalling in inflammatory and infectious diseases (ulcerative colitis and COVID-19, respectively). For ulcerative colitis, with CytokineLink, we demonstrated a significant rewiring of cytokine-mediated intercellular communication between non-inflamed and inflamed colonic tissues. For COVID-19, we were able to identify cell types and cytokine interactions following SARS-CoV-2 infection, highlighting important cytokine interactions that might contribute to severe illness in a subgroup of patients. Such findings have the potential to inform the development of novel, cytokine-targeted therapeutic strategies. CytokineLink is freely available for the scientific community through the NDEx platform and the project github repository.
细胞因子介导的细胞间通讯对于免疫反应的发展至关重要，尤其是在感染和炎症性疾病的情况下。通过释放这些小分子量的肽，源细胞可以影响靶细胞中的许多细胞内过程，包括下游其他细胞因子的分泌。然而，目前没有现成的生物信息学资源可以模拟细胞因子-细胞因子相互作用。在这项工作中，我们构建了主要组织和血细胞之间的通讯图，揭示了细胞因子介导的细胞间网络如何在稳态条件下形成。我们从文献中收集了最常见的细胞因子，并根据人类蛋白质图谱数据库中富集的共识 RNA-Seq 数据将蛋白质及其相应的受体分配给源组织和血细胞类型。为了更有信心地进行交互作用，我们整合了来自两个免疫学数据库系统——immuneXpresso 和 ImmunoGlobe 的关于细胞-细胞因子相互作用的文献信息。从整理的信息中，我们定义了两个代谢网络：一个由细胞因子连接的细胞-细胞通讯网络；以及一个细胞因子-细胞因子相互作用网络，描绘了细胞因子相互影响的潜在方式。然后，我们使用疾病状态下的表达数据，将该资源应用于揭示炎症性和传染性疾病（分别为溃疡性结肠炎和 COVID-19）中细胞因子介导的细胞间信号转导的扰动。对于溃疡性结肠炎，我们使用 CytokineLink 证明了非炎症和炎症结肠组织之间细胞因子介导的细胞间通讯的显著重布线。对于 COVID-19，我们能够确定 SARS-CoV-2 感染后的细胞类型和细胞因子相互作用，突出了可能导致部分患者重病的重要细胞因子相互作用。这些发现有可能为新型细胞因子靶向治疗策略的发展提供信息。CytokineLink 通过 NDEx 平台和项目 github 存储库免费提供给科学界。
