IRF5 promotes the progression of ulcerative colitis by regulating macrophage polarization and Toll-like receptor signaling pathway.

Interferon regulatory factor 5 (IRF5) is genetically linked to ulcerative colitis (UC) susceptibility, yet its role in intestinal inflammation remains poorly understood. Here, we detected IRF5 expression in intestinal tissues from 29 UC patients and 10 healthy controls via immunohistochemistry and immunofluorescence. We constructed DSS-induced acute colitis models in IRF5-knockout (IRF5-/-) and wild-type (IRF5+/+) mice and analyzed the transcriptome of IRF5-knockdown macrophages. IRF5 was highly upregulated in inflamed intestinal tissues of UC patients and DSS-treated mice, primarily in CD68+ macrophages. Compared with wild-type mice, IRF5-/- mice exhibited attenuated colitis, with reduced weight loss, lower disease activity index scores and milder colon shortening. Moreover, IRF5 deletion increased anti-inflammatory cytokines (IL-1rn, IL-10, IL-13, IL-17) and decreased pro-inflammatory cytokines (IL-1β, TNF). Transcriptome analysis revealed that IRF5 knockdown suppressed M1 pro-inflammatory genes (Ido1, Il12b) and upregulated the M2 marker MRC2. It also markedly inhibited TLR signaling and actin cytoskeleton regulation. Additionally, IRF5 downregulation reduced Tlr2 expression, indicating a positive feedback loop between IRF5 and TLR signaling. In summary, IRF5 exacerbates intestinal inflammation by promoting M1 macrophage polarization and activating TLR signaling, making it a promising therapeutic target for UC.