Manipulating metabolism-reprogrammed monocytic-MDSCs prevents colitis-associated dysplasia by IL-10/HIF-1α/DLL4 signaling

Dysplasia has been described in various inflammatory environments. However, the mechanisms underlying the dysplastic transformation of the intestinal epithelium and the increased risk of colorectal cancer in colitis patients are not yet fully understood. In this study, we observed that IL-10 was negatively correlated with aberrant proliferation and differentiation of colonic epithelium in colitis patients. Deficiency of myeloid IL-10 resulted in a marked accumulation of intestinal myeloid-derived suppressor cells (MDSCs) and colitis-associated dysplasia, which could be mitigated by intra-bone marrow injection of AAV9-mIL-10. Mechanistically, IL-10-deficient monocytic-MDSCs (M-MDSCs) displayed a distinct pro-inflammatory phenotype with unique metabolic properties characterized by HIF-1α overexpression-induced vibrant glycolysis. This metabolic shift was accompanied by DLL4 transcription through direct binding to its promoter and subsequently skewed the differentiation of intestinal stem cells (ISCs) toward absorptive enterocytes, thereby potentially contributing to intestinal dysplasia. Furthermore, a small-molecule drug screen identified the plant flavonoid Sophoraflavanone G (SG) as a potential DLL4 antagonist, which attenuated the abnormal lineage differentiation of ISCs and ameliorated dysplasia in colitis by inhibiting Notch1 signaling pathway overactivation. Our study highlights a critical role of myeloid IL-10 in monocyte development and homeostasis maintenance of the intestinal epithelium, suggesting potential complementary therapeutic strategies for intestinal dysplasia in colitis patients. • Loss of IL-10 in the colon may be an early biomarker for the progression of colitis to CRC. • Metabolism-reprogrammed monocytic-MDSCs with excessive DLL4 dives the colitis-associated dysplasia. • HIF-1α promotes DLL4 expression by directly binding its promoter to initiate DLL4 transcription. • IL-10 supplementation in myeloid cells and Sophoraflavanone G restrict MDSCs-induced dysplastic transformation of the intestinal epithelium in colitis.