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 that is characterized by dysregulated cytokine signaling. Treatment outcomes for patients with UC remain suboptimal despite the advent of cytokine-targeting therapies, necessitating a better understanding of the interconnected cytokine signaling networks that are perturbed in patients with UC. To address this, we undertook systems immunology modeling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed patients with UC to build complex cytokine signaling networks underpinned by putative cytokine-cytokine interactions. The generated cytokine networks effectively captured known, physiologically relevant cytokine-cytokine interactions, which we validated in vitro in colonic epithelial organoids derived from patients with UC and with organoids cocultured with innate lymphoid cells. These networks revealed several previously unrecognized aspects of UC pathogenesis. These included the identification of a cytokine subnetwork that is unique to treatment-naive patients with UC, of cytokines with altered interaction patterns across UC disease states (including IL-22, TL1A, IL-23A, and OSM), and of cytokine-cytokine interactions that were mediated by specific members of the Janus-associated kinase (JAK) family. In particular, our network analysis positioned TL1A as an important upstream regulator of TNF and IL-23A (both of which are targeted by approved UC drugs) and suggested it as a potential therapeutic target. Together, these findings open 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.