RAMP1 signaling in macrophages protects mice from concanavalin A-induced liver injury

[Speaker] Tomoyoshi Inoue:1,2
[Co-author] Yoshiya Ito:2,3, Nobuyuki Nishizawa:2,3, Humisato Otaka:1,2, Syuji Nakamoto:2,3, Seri Tsuru:2, Kyoko Hattori:2, Hideki Amano:2, Wasaburo Koizumi:1, Masataka Majima:2
1:Department of Gastroenterology, Kitasato University School of Medicine, Japan, 2:Department of Pharmacology, Kitasato University, Japan, 3:Department of Surgery, Kitasato University, Japan

Background: The significance of the crosstalk between the nervous and immune systems during inflammatory diseases has recently been appreciated. We examined the role of receptor activity-modifying protein 1 (RAMP1), a subunit of calcitonin gene-related peptide (CGRP) receptor complex in immune-mediated liver injury.

Methods: RAMP1-knockout (RAMP1-/-) mice or their wild-type counterparts (WT) were treated with Concanavalin A (Con A). The levels of RAMP1, ALT, TNFα, IFNγ and monocytes/macrophages were measured and compared.

Results: Hepatic mRNA levels of RAMP1 were enhanced and RAMP1 was expressed in hepatic and splenic macrophages. Compared with WT, RAMP1-/- mice exhibited higher levels of ALT and necrotic area at 24 h after Con A treatment. The numbers of CD68- and Ly6C-positive cells at 24 h in RAMP1-/- liver were greater than those in WT mice. Ly6Chigh/CD11bhigh cells in RAMP1-/- livers were increased as compared WT livers. The levels of TNFα and IFNγ at 1 h in liver and spleen from RAMP1-/- mice were increased as compared with WT mice. Deletion of macrophages with clodronate liposomes decreased ALT levels at 24 h in both genotypes as compared with vehicle, which was associated with down-regulation of TNFα and IFNγ at 1 h together with reduction in hepatic CD68- and Ly6C-positive cells at 24 h. In vitro, CGRP reduced TNFα and IFNγ from isolated hepatic and splenic macrophages stimulated with Con A in WT mice, but not in RAMP1-/- mice.

Conclusions: These results suggest that RAMP1 in macrophages suppresses Con A-induced liver injury through reduction in cytokines and accumulation of inflammatory cells.

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