Vascular endothelial growth factor receptor 1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by accumulation of Tregs in ulcer area

Abstract

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). 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. 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)

Keywords

• Ulcerative colitis
• VEGFR1
• Foxp3+Treg
• CXCR4