Journal
JOURNAL OF ENDODONTICS
Volume 45, Issue 10, Pages 1228-1236Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.joen.2019.06.013
Keywords
Apical lesions; cytokines; regulatory T cells; T helper; vasoactive intestinal peptide; wound healing
Categories
Funding
- Sao Paulo Research Foundation [15/25618-2, 15/24637-3]
- National Institutes of Health -National Institute of Dental and Craniofacial Research [1R01DE02105801, 1R56DE021058-01]
- National Council for Scientific and Technological Development
- Coordination for the Improvement of Higher Education Personnel
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [15/24637-3] Funding Source: FAPESP
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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 (C57BI/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.
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