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RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis
Laboratory Investigation ( IF 5 ) Pub Date : 2020-01-07 , DOI: 10.1038/s41374-019-0364-0
Seri Tsuru 1, 2, 3 , Yoshiya Ito 1, 2 , Hiromi Matsuda 3 , Kanako Hosono 1, 2 , Tomoyoshi Inoue 1 , Shuji Nakamoto 1 , Chie Kurashige 3 , Toshiaki Mishima 4 , Kazutake Tsujikawa 5 , Hirotsugu Okamoto 3 , Masataka Majima 1, 2
Affiliation  

Calcitonin gene-related peptide (CGRP) regulates inflammation via signaling through receptor activity-modifying protein (RAMP) 1. Here, we investigated the role of RAMP1 signaling in growth of lymphatic vessels during inflammation. Lymphangiogenesis in the diaphragm of RAMP1-deficient (−/−) mice or their wild-type (WT) counterparts was induced by repeated intraperitoneal injection of lipopolysaccharide (LPS). Compared with WT mice, LPS-induced lymphangiogenesis in RAMP1−/− mice was suppressed. This was accompanied by the reduced expression of vascular endothelial growth factor (VEGF)-C and VEGF-D. The number of CD4+ cells in diaphragm tissue from WT mice was greater than RAMP1−/− mice. Removing CD4+ cells attenuated lymphangiogenesis and expression of VEGF-C and VEGF-D. CD4+ cells isolated from RAMP1−/− mice exhibited reduced expression of VEGF-C and VEGF-D. The number of CD11b+ cells from RAMP1−/− mice was higher than WT mice and was associated with the upregulated expression of genes related to pro-inflammatory macrophage phenotype and downregulation of reparative macrophage phenotype-related expression. When fluorescein isothiocyanate (FITC)-dextran was injected into the peritoneal cavity, the amount of residual FITC-dextran in WT mice was lower than that in RAMP1−/− mice. The present results suggest that RAMP1 signaling in immune cells plays a critical role in inflammation-related lymphangiogenesis; therefore, it represents a novel target for controlling lymphangiogenesis.



中文翻译:

免疫细胞中的 RAMP1 信号调节炎症相关的淋巴管生成

降钙素基因相关肽 (CGRP) 通过受体活性修饰蛋白 (RAMP) 1 发出信号来调节炎症。在这里,我们研究了 RAMP1 信号在炎症过程中淋巴管生长中的作用。重复腹膜内注射脂多糖 (LPS) 可诱导 RAMP1 缺陷型 ( -/- ) 小鼠或其野生型 (WT) 小鼠隔膜中的淋巴管生成。与 WT 小鼠相比,LPS 诱导的 RAMP1 -/-小鼠淋巴管生成受到抑制。这伴随着血管内皮生长因子 (VEGF)-C 和 VEGF-D 的表达减少。WT 小鼠隔膜组织中 CD4 +细胞的数量大于 RAMP1 -/-小鼠。去除 CD4 +细胞减弱淋巴管生成和 VEGF-C 和 VEGF-D 的表达。从 RAMP1 -/-小鼠分离的CD4 +细胞表现出降低的 VEGF-C 和 VEGF-D 表达。来自 RAMP1 -/-小鼠的 CD11b +细胞数量高于 WT 小鼠,并且与促炎性巨噬细胞表型相关基因的上调表达和修复性巨噬细胞表型相关表达的下调相关。当将异硫氰酸荧光素 (FITC)-葡聚糖注入腹腔时,WT 小鼠中残留的 FITC-葡聚糖的量低于 RAMP1 -/-老鼠。目前的结果表明,免疫细胞中的 RAMP1 信号在炎症相关的淋巴管生成中起着关键作用;因此,它代表了控制淋巴管生成的新靶点。

更新日期:2020-01-07
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