Calcitonin Gene-Related Peptide Regulates Type IV Hypersensitivity through Dendritic Cell Functions

Norihisa Mikami,Ippei Otani,So-Ichiro Fukada,Yasuko Wada,Miku Takatsuji,Kazutake Tsujikawa,Yayoi Miyagi,Nagisa Hashimoto,Kaori Sueda,Hiroshi Yamamoto,Rintaro Yoshikawa,Satoshi Nishioka,Keiko Watanabe,Yusuke Ogitani,Fabrizio Mattei

doi:10.1371/journal.pone.0086367

Abstract

Dendritic cells (DCs) play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP), is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1) results in higher cytokine production in response to LPS (lipopolysaccharide). On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH) model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2+ DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2+ DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2− DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs.

Highlights

Accumulating evidence has demonstrated that the immune system is tightly regulated by nervous system-derived mediators such as hormones, cytokines, and neurotransmitters [1,2]
Calcitonin gene-related peptide (CGRP) suppresses OVA-induced delayed-type hypersensitivity (DTH) responses through these anti-inflammatory effects. These results indicate that CGRP inhibits Th1-mediated immune response through the cytokine production and function of both Dendritic cells (DCs) and Th cells, and these findings will lead to a deeper understanding of DC functions and immune regulation by CGRP
We first examined the effects of cAMP analogs on the production of IL-12, TNF-a, IL-6, and IL-10 in Bone marrow-derived dendritic cells (BMDCs) stimulated by LPS

Summary

Introduction

Accumulating evidence has demonstrated that the immune system is tightly regulated by nervous system-derived mediators such as hormones, cytokines, and neurotransmitters [1,2]. There are two isoforms of CGRP: a and b in rats and mice and I and II in humans Both CGRP isoforms bind to a specific receptor composed of receptor activity-modifying protein 1 (RAMP1) and calcitonin receptor-like receptor (CLR) [3]. Our previous studies using RAMP1-deficient mice showed that CGRP physiologically up-regulates IL-4, IL-9, and IL-17 productions by CD4+ Th cells [6,7,8,9]. CGRP inhibits the production of proinflammatory cytokines after lipopolysaccharide (LPS) administration to mice [10].

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