Vascular endothelial growth factor receptor 1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by accumulation of Tregs in ulcer area
Vascular endothelial growth factor receptor 1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by accumulation of Tregs in ulcer area
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DOI：
10.1016/j.biopha.2018.12.021
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发表时间：
2019-03-01
影响因子：
7.5
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Betto, Tomohiro;Amano, Hideki;Majima, Masataka
背景：溃疡性结肠炎（UC）是一种累及结肠的炎症性肠病。UC的发展受免疫细胞调节。以前，我们发现血管内皮生长因子受体1（VEGFR 1）酪氨酸激酶（TK）信号通过募集似乎是单核细胞谱系的VEGFR 1（+）细胞来诱导粘膜损伤的愈合。最近的研究表明，UC的发展与调节性T细胞（T细胞）的数量相关。方法：采用2.0%葡聚糖硫酸钠（DSS）诱导C57/B16 N（野生型）和VEGFR 1 TK基因敲除（VEGFR 1 TK-/-）小鼠急性结肠炎模型。VEGFR 1 TK-/-小鼠的溃疡长度和疾病活动指数（DAI）评分显著高于WT小鼠，而CD 31 mRNA和蛋白水平显著低于WT小鼠。在VEGFR 1 TK-/-小鼠中，叉头框P3（+）（Foxp 3（+））VEGFR 1（+）TcB的积累较低，白细胞介素（IL）-10和转化生长因子（TGF）-β的表达也较低。用抗叶酸受体4（FR 4）抗体处理的WT小鼠的存活率为40%，而用对照IgG处理的WT小鼠的存活率为90%。此外，用针对C-X-C趋化因子受体4型（CXCR 4）的中和抗体处理的WT小鼠显示出比使用对照抗体的WT显着更短的结肠长度。结论：VEGFR 1-TK信号通路通过VEGFR 1（+）CXCR 4（+）Foxp 3（+）TK在溃疡组织中的积累，在UC愈合和血管生成中起重要作用。
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 TK-/- 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)-beta. 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.