Elsevier

Biomedicine & Pharmacotherapy

Volume 111, March 2019, Pages 131-141
Biomedicine & Pharmacotherapy

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

https://doi.org/10.1016/j.biopha.2018.12.021Get rights and content
Under a Creative Commons license
open access

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)

Abbreviations

VEGFR1
vascular endothelial growth factor receptor 1
TK
tyrosine kinase
Tregs
regulatory T cells
WT
wild-type
Foxp3
forkhead box P3
UC
ulcerative colitis
DSS
dextran sulfate sodium
DAI
disease activity index
IL
interleukin
TGF-β
transforming growth factor
FR
folate receptor 4
CXCR4
C-X-C chemokine receptor type 4
IBD
inflammatory bowel diseases
SDF
stromal cell-derived factor
bFGF
basic fibroblast growth factor
TNF-α
tumor necrosis factor-α
HIF
hypoxia-inducible factor
PCR
polymerase chain reaction
EGF
epidermal growth factor
BM
bone marrow

Keywords

Ulcerative colitis
VEGFR1
Foxp3+Treg
CXCR4

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