Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond.

Yu Oshima,Mariko Tanaka,Nontaphat Leerach,Akane Niimura,Seiichi Munesue,Yasuhiko Yamamoto,Kenjiro Hayashi,Hiroshi Yamamoto,Kumi Kimura,Haruhiro Higashida,Ai Harashima,Hisanori Goto

doi:10.3390/ijms23042086

Abstract

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

Highlights

We recently discovered that receptor for AGEs (RAGE) present on brain vascular endothelial cells can bind oxytocin (OT) and transport it from the blood to the brain, resulting in the regulation of brain OT levels
A growing body of evidence suggests that RAGE plays a significant role in pathological processes of disease development and progression, as well as in physiological functions, including host defense, tissue regeneration, clearance of apoptotic cells, and nurturing the mother–infant bond (Table 1)
As an early communicative behavior toward their mother [59] (Figure 2). These findings indicate that membrane-bound RAGE (mRAGE)-dependent OT recruitment to the brain is essential during the early postpartum period in dams, pups, and presumably, the puerperium in humans

Summary

Introduction

Research on OT in the brain has attracted increasing attention, as the molecule plays an important role in social behaviors such as recognition, trust, antianxiety behavior, and mother–infant bonding [17,18]. Glycation is a non-enzymatic and unavoidable background reaction that occurs in all living beings and results in the formation of AGEs. Apart from AGEs, RAGE is known to interact with a series of different ligands, including high-mobility group box-1 (HMGB1), Gram-negative bacterial cell wall lipopolysaccharides (LPS), S100 proteins, complement component C3, phosphatidylserine (PS), and amyloid-β. The extracellular RAGE antagonists such as low molecular weight heparin (LMWH), azeliragon (TTP488), papaverine, N-Benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1), and RAGEantagonist peptide (RAP) are known to inhibit disease development [25,26,27,28,29,30]

Role of RAGE in Physiological and Pathological Processes

Relevant Findings

RAGE Isoforms

RAGE and OT Nurtures the Mother–Infant Bonding

Conclusions