VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease
VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease
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DOI：
10.1172/jci72189
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Danese, Silvio
中科院分区：
文献类型：
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作者：
D'Alessio, Silvia;Correale, Carmen;Danese, Silvio
克罗恩病（CD）和溃疡性结肠炎（UC）是病因不明的慢性炎症性肠病（IBD），与异常的粘膜免疫反应有关。在IBD中观察到新血管生成和血管损伤沿着增加的淋巴管生成。虽然IBD中血管生成的致病作用已得到很好的表征，但尚不清楚淋巴管生成增加如何或是否促进疾病。在这里，我们确定，增强淋巴管生成和淋巴功能减少实验性IBD。具体来说，我们证明了腺病毒诱导的淋巴管生成因子VEGF-C提供了显着的保护，对急性和慢性结肠炎的发展，在2个不同的动物模型。观察到VEGF-C依赖性保护与增加的炎性细胞动员和从发炎结肠到引流淋巴结的细菌抗原清除相结合。此外，我们发现，VEGF-C/VEGFR 3途径调节巨噬细胞（MO）的可塑性和激活在培养的M Phi s和体内，赋予一个混合M1-M2表型。VEGF-C的保护功能是通过STAT 6依赖的方式在慢性实验性结肠炎期间通过所谓的解决M Phi s来介导的。总之，这些发现揭示了淋巴系统对肠道炎症发病机制的贡献，并表明用VEGF-C纠正淋巴功能缺陷具有作为IBD治疗策略的潜力。
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C-dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (MO) plasticity and activation both in cultured M Phi s and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving M Phi s during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD.