RAMP1 signaling in immune cells regulates lymphangiogenesis in the diaphragm during peritonitis

• Published in: 日本薬理学会年会要旨集 p. 1-YIA-09
• Main Authors: 津留, 世里, 伊藤, 義也, 細野, 加奈子, 松田, 弘美, 蔵重, 千絵, 井上, 智仁, 中本, 修司, 大高, 史聖, 岡本, 浩嗣, 馬嶋, 正隆
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2019
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.92.0_1-YIA-09

Lymphatic vessels in the diaphragm are essential for draining peritoneal fluid during peritonitis. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, promotes wound-induced lymphangiogenesis via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. In this study, we examined the functional role of RAMP1 in inflammation-induced lymphangiogenesis in the diaphragm. RAMP1-knockout mice (RAMP1 KO) or their wild-type counterparts (WT) were intraperitoneally injected with LPS. Compared with WT, RAMP1 KO exhibited less lymphangiogenesis associated with reduced expression of VEGF-C and VEGF-D and with enhanced expression of Th1-related cytokines including TNF and IFN. The numbers of CD4+ cells in WT were greater than those in RAMP1 KO. RAMP1 was expressed in CD4+ cells, which also expressed VEGF-C and VEGF-D. Isolated splenic CD4+ cells stimulated with LPS enhanced expression of VEGF-C and VEGF-D in a RAMP-1 dependent manner. Deletion of CD4+ cells with an anti-CD4 antibody suppressed lymphangiogenesis. Functional assays with an intraperitoneal injection of fluorescein isothiocyanate (FITC) revealed delayed peritoneal fluid drainage in diaphragm of WT as compared with RAMP1 KO. These results suggest that RAMP1 signaling in T cells plays a critical role in LPS-induced lymphangiogenesis and lymphatic dysfunction in the diaphragm.