Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation.
Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation.
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DOI：
10.1016/j.ajpath.2017.07.019
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发表时间：
2017-11
期刊：
影响因子：
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通讯作者：
Jie-gang Yang;Yan-fang Sun;Ke-fei He;Jian-Gang Ren;Zhuo-Jue Liu;Bing Liu;W. Zhang;Yi-Fang Zhao
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文献类型：
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作者：
Jie-gang Yang;Yan-fang Sun;Ke-fei He;Jian-Gang Ren;Zhuo-Jue Liu;Bing Liu;W. Zhang;Yi-Fang Zhao
炎症相关的三级淋巴器官的形成促进人类淋巴管畸形（LM）的发展。然而，在淋巴母细胞瘤中，作为三级淋巴器官形成的关键介质的光毒素（LT）和LT相关的诱导配体的作用尚未确定。在此，我们发现LT和LT相关的诱导配体通过激活NF-κ B途径促进淋巴管内皮细胞（LEC）增殖，从而促进LM的发展。与正常皮肤相比，LMs中LTs及其受体的表达增加，尤其是感染的LMs。LMs LEC中p65、p52和RelB的核转位表明经典和替代NF-κ B通路的激活。Pearson相关分析和聚类分析提示LEC增殖与NF-κ B活化密切相关。体外实验表明，LT可通过激活NF-κ B促进人皮肤LEC（HdLEC）增殖。此外，脂多糖（LPS）上调HdLEC中LT受体的表达，导致对LT的敏感性增加。LT受体的抑制阻碍了LPS增强的HdLEC增殖，表明LT途径在炎性淋巴管生成中的关键作用。此外，LM大鼠模型的证据表明，LT α和LPS促进LEC增殖，从而促进LM的发展。通过抗LT α和抗光敏素β受体的中和抗体阻断LT途径可减缓疾病的发展。总之，我们目前的研究表明，在LEC LT信号通路的激活有助于LM的进展。
Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover,in vitrodata demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin β receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.