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

Marton Olbei,Isabelle Hautefort,Matthew Madgwick,Tamas Korcsmaros,Agatha Treveil,Balazs Bohar,John P Thomas,Lejla Gul,Dezso Modos,Luca Csabai

doi:10.3390/cells10092242

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.

Highlights

Cytokines are the key mediators of intercellular communication
We built the CytokineLink network resource based on cytokine–receptor interactions found in the literature [1] and the integrated OmniPath resource [10]
We have introduced a new biological network resource, CytokineLink, enabling the detailed analysis of intercellular communication mediated by cytokines

Summary

Introduction

Cytokines are low molecular weight peptides (5–20 kDa) released by a wide repertoire of cell types including immune cells, epithelial cells, endothelial cells, fibroblasts, and other stromal cells. They enable coordinated autocrine, paracrine, and even endocrine homeostatic functions to occur within the body [1]. Cytokines effectively regulate all physiological processes in the human body ranging from embryonic development, to angiogenesis, to haemostasis, and innate and adaptive immunity Cytokines can achieve such diverse and wide-ranging effects because they exhibit pleiotropy (i.e., a single cytokine can cause different biological effects and can act on different cell types) and redundancy (i.e., a variety of cytokines can activate the same signalling pathways) [3]

Methods

Results

Conclusion