Galectin-3 Plays an Important Role in Preterm Birth Caused by Dental Infection of Porphyromonas gingivalis

Mutsumi Miyauchi,Katsuyuki Kozai,Shinnichi Sakamoto,Chanbora Chea,Min Ao,Hisako Furusho,Toshihiro Inubushi,Atsuhiro Nagasaki,Toshinori Ando,Takashi Takata

doi:10.1038/s41598-018-21072-y

Abstract

Dental infection is risk for preterm birth (PTB) through unclear mechanisms. We established a dental infection-induced PTB mouse model, in which Porphyromonas gingivalis (P.g.) induced PTB by 2 days. We analysed pathogenic factors contributing to PTB and their effects on trophoblasts in vitro. TNF-α, IL-8, and COX-2 were upregulated in P.g.-infected placenta. Galectin-3 (Gal-3), an immune regulator, was significantly upregulated in placenta, amniotic fluid, and serum. In vitro, P.g.-lipopolysaccharide (P.g.-LPS) increased TNF-α and Gal-3 in trophoblasts via NF-κB/MAPK signalling. Gal-3 inhibition significantly downregulated P.g.-LPS-induced TNF-α production. TNF-α upregulated Gal-3. Gal-3 also increased cytokines and Gal-3 through NF-κB/MAPK signalling. Moreover, Gal-3 suppressed CD-66a expression at the maternal-foetal interface. Co-stimulation with Gal-3 and P.g.-LPS upregulated cytokine levels, while Gal-3 plus Aggregatibacter actinomycetemcomitans (A.a.)- or Escherichia coli (E. coli)-LPS treatment downregulated them, indicating the critical role of Gal-3 especially in P.g. dental infection-induced PTB. P.g.-dental infection induced PTB, which was associated with Gal-3-dependent cytokine production. New therapies and/or diagnostic systems targeting Gal-3 may reduce PTB.

Highlights

Production of prostaglandins, TNF-α, IL-6, and IL-8, which leads to more frequent and intense uterine contractions with consequential PTB6,7
We demonstrated that P.g. remained alive inside the pulp chamber, reproduced long enough to induce periapical periodontitis, and maintained upregulated LPS levels in the serum[22]
We confirmed the establishment of chronic, low-grade systemic inflammation, including upregulated TNF-α, IL-17, IL-6, and IL-1β serum levels at 6-weeks post-P.g. infection, the time of mating[16]

Summary

Introduction

Production of prostaglandins, TNF-α, IL-6, and IL-8, which leads to more frequent and intense uterine contractions with consequential PTB6,7. In 1996, the results from a case-control study performed by Offenbacher et al suggested that maternal periodontal disease was associated with a 7.9-fold increased risk for PTB/low birth weight[10]. Several experimental studies have revealed that Porphyromonas gingivalis (P.g.), a main periodontal pathogen, can invade the placental-fetal barrier to induce pregnancy complications in rodents and rabbit animal models[13,14,15]. We established a dental infection-induced PTB mouse model that showed long-term low-grade inflammation, which ideally imitates the clinical condition of pregnant women with periodontitis. In P.g.-infected placenta, upregulation of inflammatory mediators such as TNF-α and COX-2 (inducible synthetase of prostaglandins) was observed, which can promote the initiation of labour[16]. We identified an interesting immune-regulatory molecule, Galectin-3 (Gal-3), which was upregulated in P.g.-infected placental tissue compared control placentas. The underlining mechanisms, in which Gal-3 induces PTB, were studied a using human trophoblast cell line

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Conclusion