RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice

Mishima, Toshiaki; Yoshiya, Ikuto; Nishizawa, Nobuyuki; Aoki, Hideki; Tsujikawa, Kazutake; Miyaji, Kagami; Watanabe, Masahiko; Murakami, Masataka

doi:10.1016/j.jss.2017.05.124

Cited by 28 publications

(31 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the roles of sensory neuron-immune interactions in response to sterile tissue damage are not fully understood, we showed previously that RAMP1 signaling regulates inflammation by suppressing inflammatory mediators released from immune cells such as dendritic cells, macrophages, and lymphocytes [ 9 , 10 ]. CGRP also contributes to wound healing and secondary lymphedema by affecting RAMP1 signaling in macrophages [ 21 , 22 ]. CGRP is widely distributed in the central and peripheral nervous system, and is released from the sensory neurons [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

et al. 2018

Self Cite

View full text Add to dashboard Cite

The significance of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.

show abstract

Section: Discussionmentioning

confidence: 99%

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although the roles of sensory neuron-immune interactions in response to sterile tissue damage are not fully understood, we showed previously that RAMP1 signaling regulates inflammation by suppressing inflammatory mediators released from immune cells such as dendritic cells, macrophages, and lymphocytes [9,10]. CGRP also contributes to wound healing and secondary lymphedema by affecting RAMP1 signaling in macrophages [21,22]. These findings indicate that CGRP secreted from endings of sensory nerve fibers regulates immune function via RAMP1 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…CGRP acts on immune cells directly and regulates their production of cytokines in inflammatory lesions [23]. Previously, we reported that RAMP1 is expressed by T cells [10,24], dendritic cells [9], and macrophages [21,22], and that RAMP1 expression by these immune cells is essential for development of inflammation during endotoxemia and colitis. Here, we show that RAMP1 is expressed by hepatic and splenic macrophages and by splenic T cells.…”

Section: Discussionmentioning

confidence: 99%

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

Inoue

Yoshiya

Nishizawa

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

The significanceF of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.

show abstract

“…Lymphangiogenesis was estimated by calculating lymphatic vessel density (LVD) and lymphatic vessel area (LVA), as described previously. 25 Briefly, lymphatic vessels were stained with anti-LYVE-1 antibody, and the individual lymphatic vessels within the area were counted as for CD31 + cells as described above. The results are expressed as the number of vessels per square millimetre (LVD/mm 2 ).…”

Section: Determination Of Vessel Densitymentioning

confidence: 99%

“…[18][19][20] Furthermore, we reported that the CGRP/RAMP1 axis in the nervous system regulates angiogenesis in tumour tissues 21 and in injured tissues caused by gastric ulcers 22 and ischaemia. 23 CGRP/RAMP1 also plays a role in lymphangiogenesis in mice with skin wounds 24 and with inflammation in the tail 25 and diaphragm. 26 In these pathological conditions, CGRP/RAMP1 signalling facilitates angiogenesis and lymphangiogenesis by inducing pro-angiogenic/lymphangiogenic growth factor production by accumulated immune cells and fibroblasts.…”

Section: Introductionmentioning

confidence: 99%