Downregulation of IFIT3 Relieves the Inflammatory Response in Ulcerative Colitis via Selectively Regulating Macrophage M1 Polarization and the STAT1/2 Signaling Pathway

Purpose: Ulcerative colitis (UC) is an inflammatory condition of the colon. Interferon-induced protein with tetratricopeptide repeat 3 (IFIT3), a member of the IFIT family, is known to be associated with Antiviral immunity and cellular regulation. However, the functional and molecular mechanisms by which IFIT3 affects the occurrence and development of UC have not been reported.

Patients and methods: Intestinal mucosa samples were collected from 22 UC patients and 20 healthy controls. After immunohistochemical staining and image analysis, the correlation between IFIT3 expression and clinical characteristics of UC patients was analyzed. Subsequently, we applied a dextran sulfate sodium (DSS)-induced colitis model in adeno-associated virus 9 -mediated IFIT3 silencing mice. Inflammatory cytokines and signal pathway molecules were examined. Moreover, THP-1 cells, lipopolysaccharide (LPS) and upadacitinib (UPA) were used in vitro experiments, and various assays were performed to evaluate IFIT3 expression, cellular responses, and signaling pathways.

Results: First, our results demonstrated that IFIT3 was upregulated in colon tissues of UC patients and was positively correlated with the Mayo clinical score and fecal calprotectin levels. Second, knockdown of IFIT3 significantly attenuated the intestinal inflammatory response and reduced phosphorylated signal transducer and activator of transcription 1 and 2 (pSTAT1 and pSTAT2) protein levels in DSS-induced UC mice. Further mechanistic studies revealed that IFIT3 regulated LPS-induced M1 polarization in THP-1 macrophages by modulating the STAT1 signaling pathway. In addition, UPA exerted anti-inflammatory effects in vitro, to some extent, through the inhibition of IFIT3 expression.

Conclusion: Our findings highlight the role of IFIT3 in inflammatory responses and macrophage polarization in colitis, suggesting that IFIT3 may be a promising target for UC treatment.

inflammatory response; interferon-induced protein with tetratricopeptide repeat 3; macrophage; signal transducer and activator of transcription 1/2; ulcerative colitis.