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