RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis

• Published in: Laboratory investigation 2020-05, Vol.100 (5), p.738-750
• Main Authors: Tsuru, Seri, Ito, Yoshiya, Matsuda, Hiromi, Hosono, Kanako, Inoue, Tomoyoshi, Nakamoto, Shuji, Kurashige, Chie, Mishima, Toshiaki, Tsujikawa, Kazutake, Okamoto, Hirotsugu, Majima, Masataka
• Format: Article
• Language: English
• Subjects: 14/1; 14/19; 14/34; 38/77; 631/1647/767/1424; 631/250/256/2515; 64/60; Animal tissues; Animals; Blood vessels; Calcitonin; Calcitonin gene-related peptide; CD11b antigen; CD4 antigen; Dextran; Dextrans; Diaphragm; Diaphragm - metabolism; Fluorescein; Fluorescein isothiocyanate; Gene expression; Growth factors; Immune system; Inflammation; Inflammation - genetics; Inflammation - metabolism; Laboratory Medicine; Lipopolysaccharides; Lymphangiogenesis - genetics; Lymphangiogenesis - physiology; Lymphatic drainage; Lymphatic system; Lymphatic Vessels - metabolism; Macrophages; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Pathology; Peptides; Peritoneal fluid; Peritoneum; Phenotypes; Proteins; Receptor activity modifying proteins; Receptor Activity-Modifying Protein 1 - genetics; Receptor Activity-Modifying Protein 1 - metabolism; Receptors; Rodents; Signal Transduction - genetics; Signaling; T-Lymphocytes - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factors - genetics; Vascular Endothelial Growth Factors - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-019-0364-0

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.