The interleukin 22–oncostatin M axis promotes intestinal inflammation and tumorigenesis [Colon_Tissue_BulkRNA-seq]

Multicellular cytokine networks regulate the onset of intestinal inflammation and colitis-associated cancer (CAC). Interleukin 22 (IL-22) promotes epithelial cell recovery but can also drive inflammation and tumorigenesis. We demonstrate that IL-22 from innate lymphoid cells activates STAT3 and increases OSM receptor expression in intestinal epithelial cells. This activation leads to sustained STAT3 activity via OSM, promoting inflammation and tumorigenesis. Deleting the OSM receptor or blocking OSM pharmacologically mitigates colitis and CAC. Our findings highlight the IL-22-OSM axis as a potential therapeutic target for these conditions. In this study, we investigated the role of OSM signaling in various resident colon cell types during intestinal inflammation. We generated cell type-specific OSMR-deficient mice by crossing Osmr^fl/fl with Villin^creERT2, Col1a2^creERT2, or Cdh5^cre to delete OSMR in epithelial, stromal, and endothelial cells, respectively. The resulting lines included Villin^creERT2 Osmr^fl/fl (IECΔOsmr), Col1a2^creERT2 Osmr^fl/fl (StomaΔOsmr), and Cdh5^cre Osmr^fl/fl (EndoΔOsmr). Prior to inducing colitis, these mice and their controls were co-housed for at least four weeks. Col1a2^creERT2 and Villin^creERT2 Osmr^fl/fl mice, as well as Villin^creERT2 Stat3^fl/fl mice, were treated with 75 mg/kg body weight of tamoxifen administered intraperitoneally daily for one week, following the Jackson Laboratory protocol. Control mice, either cre+ Osmr^fl/wt or Osmr^fl/fl without creERT2, also received tamoxifen. Colitis was induced by orally inoculating the mice with 1 × 10^8 CFU of H. hepaticus for two consecutive days, followed by weekly 1 mg injections of anti-IL10R antibody. On day 21 after colitis induction, colonic tissues from the proximal, mid, and distal colon were collected. For bulk RNA sequencing analysis of colonic tissue from IECΔOsmr, StomaΔOsmr, and EndoΔOsmr, as well as their respective controls, tissues were initially preserved in RNA Later (Qiagen). RNA was isolated using the RNeasy Mini Kit (Qiagen), following the manufacturer's protocol. The subsequent procedures were conducted at Novogene, where sequencing was performed on a HiSeq X sequencer to generate 150 bp paired-end reads.