Y-ECCO Literature Review: John Thomas

The pathogenesis of Inflammatory Bowel Disease (IBD) is characterised by dysregulated cytokine networks, which orchestrate intercellular communication between immune, stromal and epithelial compartments [1]. The traditional dogma in IBD posited that Th1-mediated responses (involving IL-2, IL-12 and IFNγ) predominated in Crohn’s Disease (CD), whereas excessive Th2-mediated responses (involving IL-4, IL-5 and IL-13) prevailed in Ulcerative Colitis (UC) [2]. Mounting evidence that multiple cytokines contribute to both forms of IBD has now dispelled this paradigm. For instance, the efficacy of ustekinumab (anti-IL-12/23p40), which targets Th1 and Th17 responses, in both UC [3] and CD [4] underscores shared cytokine signalling mechanisms.

Within this evolving landscape, oncostatin M (OSM), a member of the IL-6 cytokine family [5], recently emerged as a key pathogenic cytokine. In 2017, West and colleagues showed that OSM is highly expressed in inflamed colonic mucosa of IBD patients compared with controls and that elevated mucosal OSM predicts resistance to anti-TNF therapy [6]. They demonstrated that OSM is produced by CD4+ T cells and HLA-DR+ antigen-presenting cells, while its receptor (OSMR) is expressed mainly on non-haematopoietic stromal cells. These findings suggested that immune–stromal signalling driven by OSM underpins anti-TNF resistance in IBD.

In the study addressed in this literature review, Cineus and colleagues considerably advance our understanding of OSM biology through integrative experiments spanning murine models, organoids and human expression data.

First, the authors characterised shifts in Osm and Osmr expression during intestinal inflammation using two murine models: the Helicobacter hepaticus plus anti-IL-10 receptor model and Citrobacter rodentium infection. They found that both Osm and Osmr were rapidly induced at colitis onset and remained persistently elevated. While Osm was broadly expressed across haematopoietic populations in healthy mice, production shifted to inflammatory monocytes, neutrophils and dendritic cells in colitic mice. Osmr, largely confined to stromal cells in the non-inflamed state, showed a modest but significant increase in intestinal epithelial cells (IECs) during colitis, where expression correlated with histological severity. Human intestinal biopsies also revealed elevated epithelial OSMR expression in IBD patients compared with non-IBD controls.

To interrogate the functional effects of Osmr during colitis, the authors employed a series of elegant, reductionist experiments in mice using conditional deletion strategies to selectively ablate Osmr expression in epithelial, stromal and endothelial compartments. Strikingly, conditional deletion of Osmr in IECs, but not in stromal or endothelial cells, ameliorated colitis, suggesting that epithelial OSM signalling plays a critical role in propagating inflammation in colitis. This is a notable departure from the previous emphasis on OSM signalling between immune–stromal compartments.

Having identified a pathogenic role for epithelial OSM signalling in colitis, the authors next investigated its upstream regulation. Using murine colonic epithelial organoids, they systematically tested cytokines and other inflammatory stimuli, identifying IL-22 as the most potent inducer of Osmr in IECs. This corroborated with positive correlations observed between OSMR expression in four independent IBD patient cohorts and a recently characterised IL-22-responsive gene signature derived from human colonic epithelial organoids [7]. In vivo experiments involving IL-22 knockout mice, wild-type mice treated with IL-22 neutralising antibodies and IEC-specific IL-22 receptor knockouts all exhibited impaired OSMR induction and attenuated colitis. Further mechanistic dissection revealed that IL-22 acted via STAT3, as IECs deficient in Stat3 failed to upregulate Osmr upon IL-22 stimulation. Group 3 innate lymphoid cells (ILC3s) were identified as the primary source of IL-22 in the inflamed colon, with IL-23 inhibition reducing IL-22 production, epithelial Osmr expression and disease activity. The functional consequences of OSMR activation in IECs were subsequently explored. IEC-specific Osmr deficiency blunted STAT3 phosphorylation, reduced inflammatory gene expression and limited immune infiltration. These findings demonstrated a pathogenic IL-23–IL-22–OSMR–STAT3 axis, linking ILC3-derived cytokine signals to colonic epithelial inflammatory responses.

Finally, Cineus and colleagues investigated OSMR in colitis-associated cancer (CAC). OSMR was highly expressed in tumour epithelial and stromal cells but absent from adjacent normal tissue both in the azoxymethane/dextran sodium sulphate (AOM/DSS) model of CAC and in human CAC samples. Genetic deletion of Osm reduced tumour burden, as did anti-OSM therapy or IEC-specific Osmr ablation after tumour initiation. Anti-OSM therapy also decreased STAT3 phosphorylation in adenomas. Blockade of IL-22 or IL-12/23 reduced Osmr expression in adenoma epithelial cells, while IL-12/23 inhibition also lowered Il22 expression. Collectively, these findings unveiled the IL-23–IL-22–OSMR–STAT3 axis as both a mediator of inflammation and a promoter of CAC tumorigenesis.