RT Journal Article
SR Electronic
T1 RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 357582
DO 10.1101/357582
A1 Tomoyoshi Inoue
A1 Yoshiya Ito
A1 Nobuyuki Nishizawa
A1 Koji Eshima
A1 Ken Kojo
A1 Fumisato Otaka
A1 Tomohiro Betto
A1 Sakiko Yamane
A1 Kazutake Tsujikawa
A1 Wasaburo Koizumi
A1 Masataka Majima
YR 2018
UL http://biorxiv.org/content/early/2018/06/27/357582.abstract
AB 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.