Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions

Michelle de Campos Soriani Azevedo; Thiago Pompermaier Garlet; Carolina Favaro Francisconi; Priscila Maria Colavite; André Petenuci Tabanez; Jessica Lima Melchiades; Ana Paula Favaro Trombone; Charles Sfeir; Steven Little; Renato Menezes Silva; Gustavo Pompermaier Garlet

doi:10.1016/j.joen.2019.06.013

Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions

J Endod. 2019 Oct;45(10):1228-1236. doi: 10.1016/j.joen.2019.06.013. Epub 2019 Aug 8.

Affiliations

¹ Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
² Department of Structural and Molecular Biology and Genetics, State University of Ponta Grossa, Ponta Grossa, Parana, Brazil.
³ Universidade do Sagrado Coração, Bauru, São Paulo, Brazil.
⁴ Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁵ McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁶ Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.
⁷ Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil. Electronic address: garletgp@usp.br.

PMID: 31402064
DOI: 10.1016/j.joen.2019.06.013

Abstract

Introduction: The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions.

Methods: Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects.

Results: VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4.

Conclusions: Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.

Keywords: Apical lesions; T helper; cytokines; regulatory T cells; vasoactive intestinal peptide; wound healing.

MeSH terms

Animals
Humans
Mice
Mice, Inbred C57BL
Periapical Granuloma* / metabolism
T-Lymphocytes, Regulatory
Th17 Cells
Vasoactive Intestinal Peptide* / metabolism

Substances

Vasoactive Intestinal Peptide