RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis
RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis
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免疫细胞中的 RAMP1 信号传导调节炎症相关的淋巴管生成
DOI：
10.1038/s41374-019-0364-0
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发表时间：
2020
影响因子：
5
通讯作者：
Majima Masataka
中科院分区：
文献类型：
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作者：
Tsuru Seri;Ito Yoshiya;Matsuda Hiromi;Hosono Kanako;Inoue Tomoyoshi;Nakamoto Shuji;Kurashige Chie;Mishima Toshiaki;Tsujikawa Kazutake;Okamoto Hirotsugu;Majima Masataka
降钙素基因相关肽(CGRP)通过受体活性修饰蛋白(RAMP)1信号调节炎症。在此，我们研究了RAMP1信号在炎症过程中淋巴管生长中的作用。用重复注射脂多糖的方法诱导RAMP1基因缺陷(−/−)或野生型(WT)小鼠的膈淋巴管生成。与WT小鼠相比，−/−小鼠体内脂多糖诱导的淋巴管生成受到抑制。伴随着血管内皮生长因子-C和血管内皮生长因子-D表达的降低。WT小鼠横隔组织中CD_4~+细胞数量高于−/−小鼠。去除CD4+细胞可抑制淋巴管生成和血管内皮生长因子C、D的表达。从−/−小鼠体内分离的CD_4+细胞表达血管内皮生长因子-C和血管内皮生长因子-D的水平降低。−/−小鼠CD11b+细胞数量高于WT小鼠，与促炎巨噬细胞表型相关基因表达上调和修复性巨噬细胞表型相关基因表达下调有关。异硫氰酸荧光素-葡聚糖腹腔注射后，WT小鼠体内的FITC-葡聚糖残留量低于−/−小鼠。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关键作用，因此，它是控制淋巴管生成的一个新的靶点。
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.