Decoding Cytokine Networks in Ulcerative Colitis to Identify Pathogenic Mechanisms and Therapeutic Targets

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract characterised by dysregulated cytokine signalling. Despite the advent of advanced therapies targeting cytokine signalling, treatment outcomes for UC patients remain suboptimal. Hence, there is a pressing need to better understand the complexity of cytokine regulation in UC by comprehensively mapping the interconnected cytokine signalling networks that are perturbed in UC patients. To address this, we undertook systems immunology modelling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed UC patients to build complex cytokine signalling networks underpinned by putative cytokine–cytokine interactions. The generated cytokine networks effectively captured known physiologically relevant cytokine–cytokine interactions which we recapitulated in vitro in UC patient-derived colonic epithelial organoids. These networks revealed new aspects of UC pathogenesis, including a cytokine subnetwork that is unique to treatment-naive UC patients, the identification of highly rewired cytokines across UC disease states (IL22, TL1A, IL23A, and OSM), JAK paralogue-specific cytokine-cytokine interactions, and the positioning of TL1A as an important upstream regulator of TNF and IL23A as well as an attractive therapeutic target. Overall, these findings open up several avenues for guiding future cytokine-targeting therapeutic approaches in UC, and the presented methodology can be readily applied to gain similar insights into other immune-mediated inflammatory diseases (IMIDs). One Sentence Summary A systems immunology map of cytokine interaction networks in ulcerative colitis reveals novel insights into disease pathogenesis, with potential to guide future cytokine-targeting therapeutic strategies.