CytokineLink: A Cytokine Communication Map to Analyse Immune Responses-Case Studies in Inflammatory Bowel Disease and COVID-19

Abstract

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.

Keywords: COVID-19; Cytoscape; NDEx; cytokine; inflammatory bowel disease; network; resource.

Figure 1

The construction steps and main sources of CytokineLink. Cytokine–receptor data was obtained from OmniPath and a relevant literature source. RNA enrichment data was downloaded from the Human Protein Atlas to assign cytokines and cytokine receptors to source tissue and cell types. The combination of cytokine–receptor interactions, and tissue/cell–cytokine/receptor interactions was used to generate base networks containing tissue–cytokine–receptor interactions, from which abstracted meta-edges were created. The cell–cytokine associations were further annotated using information from two systems of immunology databases, immuneXpresso and ImmunoGlobe. The cell–cell meta-edges show the intercellular interactions mediated by the individual cytokines. The cytokine–cytokine edges indicate the potential ways by which the production of a cytokine can alter the production of another, by binding to its receptor carried by a cell type expressing the secondary cytokine.

Figure 2

Cytokine-specific rewiring of intercellular interactions in ulcerative colitis. Global cell–cell interaction (a) and cytokine-specific cell–cell interaction (b) networks in inflamed and non-inflamed UC tissues. (a) Global cell–cell interaction networks showed only a few differences in the cell types interacting with each other between non-inflamed and inflamed UC states. More interactions between inflammatory fibroblasts and type 1 dendritic cells (DC1s) were present in inflamed UC compared to non-inflamed UC. The size of the nodes corresponds to the degree. (b) Cytokine-specific cell–cell interaction networks revealed more notable differences between non-inflamed and inflamed UC states, particularly with the cytokines IL10 and TFB1. IL10 was found to be produced by regulatory T cells (Tregs) in both inflamed and non-inflamed UC tissues, but in non-inflamed conditions, IL10 was found to interact with additional cell types including innate lymphoid cells (ILCs) and type 2 dendritic cells (DC2s). In inflamed UC, TGFB1 signalling shifted to interactions occurring mostly between DC1s and inflammatory fibroblasts, myofibroblasts, DC2s, and CD8 lamina propria (LP) T cells.

Figure 3

Metanetworks of cytokines increased in COVID-19 patients. (a) Intercellular interactions involving cytokines elevated in COVID-19 patients. (b) Intercellular interactions mediated by IL4 and IL5. (c) Combined intercellular network of cytokines elevated in COVID-19 patients, and intercellular interactions mediated by IL4 and IL5. (d) Cytokine–cytokine involving cytokines elevated in COVID-19 patients. (e) Cytokine–cytokine interactions involving IL4 and IL5. (f) Combined cytokine–cytokine network. The IL4-IL12 interaction is highlighted with dashed lines. IL4 is increased in severe COVID-19, potentially repressing IL12, whose levels are comparable to healthy controls in severe cases [37,38]. Mutual edges were collapsed, shown with arrows on both ends to reduce complexity.