Abstract

Inflammatory bowel disease (IBD) presents significant therapeutic challenges. The immune regulatory protein TIPE2 is a risk factor for inflammatory diseases including IBD, but its potential as a therapeutic target remains undefined. Here, we developed a replication-defective adenovirus encoding TIPE2-specific shRNA (AdV-shTIPE2) to knock down TIPE2 gene expression in mice, and tested its therapeutic potential for treating dextran sulfate sodium (DSS)-induced colitis. Intravenous AdV-shTIPE2 administration conferred profound protection against colitis as judged by body weight loss, fecal bleeding, and colon length changes. Histological analyses also revealed significant preservation of epithelial integrity, and diminished pathological damage in AdV-shTIPE2-treated mice. Mechanistically, TIPE2 knockdown limited infiltration of CD45 + leukocytes, particularly CD11b + Ly6G - myeloid cells, and reduced colonic inflammatory cytokine gene expression. Analysis of human IBD bulk and single-cell transcriptomic data confirmed TIPE2 upregulation and identified a distinct TIPE2-expressing monocyte subpopulation highly enriched in human intestinal lesions of IBD patients, demonstrating a conserved pathogenic TIPE2-myeloid axis across species. Together, these results validate TIPE2-driven inflammatory cell infiltration as a key driver of IBD and establish targeted TIPE2 silencing as a promising therapeutic strategy worthy of future clinical investigation.