Ulcerative Colitis (UC) is an inflammatory bowel disease that affects the colon. The development of UC is regulated by immune cells. Previously, we showed that vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase (TK) signaling induces healing of mucosal damage by recruiting VEGFR1⁺ cells appear to be lineage monocyte cells. Recent studies show that development of UC correlates with the number of regulatory T cells (Tregs). Here, we investigated whether VEGFR1-TK signaling induces healing of UC via accumulation of Tregs or not.

Acute colitis was induced in C57/Bl6N (wild-type [WT]) and VEGFR1 T K knockout (VEGFR1 T K^−/−) mice by administration of 2.0% dextran sulfate sodium (DSS).

Total colon length in VEGFR1 T K^−/− mice was shorter than that in WT mice. The ulcer length and the disease activity index (DAI) score were significantly higher in VEGFR1 T K^−/− mice than in WT mice, whereas CD31 mRNA and protein levels were significantly lower. Accumulation of forkhead box P3⁺ (Foxp3⁺) VEGFR1⁺ Tregs was lower in VEGFR1 T K^−/− mice, as was expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. The survival rate of WT mice treated with an anti-folate receptor 4 (FR4) antibody was 40%, while that of WT mice treated with control IgG was 90%. Moreover, WT mice treated with a neutralizing antibody against C-X-C chemokine receptor type 4 (CXCR4) showed significantly shorter colon length than WT with control antibody. In VEGFR1 T K^−/−, infiltration of Foxp3⁺ Tregs expressing VEGFR1 and CXCR4 into ulcerated areas was lower than that in WT mice.

VEGFR1-TK signaling plays a critical role in UC healing and angiogenesis via accumulation of VEGFR1⁺CXCR4⁺Foxp3⁺ Tregs in ulcerated tissue. (264 words)