Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions |
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| Institution: | 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;6. Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;5. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;7. Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas;1. Department of Endodontics, São Leopoldo Mandic Dental Research Center, Campinas, São Paulo, Brazil;2. Department of Endodontics, School of Dentistry, Pontifical Catholic University of Campinas, Campinas, São Paulo, Brazil;1. Department of Restorative Dentistry, Endodontics Division, UNESP-UNIV Estadual Paulista, São José dos Campos Dental School, São José dos Campos, São Paulo, Brazil;2. Department of Restorative Dentistry, Endodontics Division, Piracicaba Dental School, State University of Campinas, UNICAMP, Piracicaba, São Paulo, Brazil;3. Department of Semiology and Clinics, Periodontics Division, Federal University of Pelotas, School of Dentistry, UFPel, Pelotas, Rio Grande do Sul, Brazil;4. Department of Restorative Dentistry, Endodontics Division, Amazonas State University, Manaus, Amazonas, Brazil;1. Department of Endodontics, Universitat Internacional de Catalunya, Barcelona, Spain;2. Department of Conservative Dentistry and Endodontics, Swargiya Dadasaheb Kalmegh Dental College and Hospital, Nagpur, India;3. Department of Conservative Dentistry and Endodontics, Nair Hospital Dental College, Mumbai, Maharashtra, India;4. Private Practice, Hill Rd, Bandra West, Mumbai, Maharashtra, India;1. Department of Orthodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China;2. Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;3. Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai, China;1. Postgraduate Program, School of Dentistry, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil;2. Department of Specific Formation, School of Dentistry, Fluminense Federal University, Nova Friburgo, Rio de Janeiro, Brazil;3. Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil |
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| Abstract: | IntroductionThe 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.MethodsPeriapical 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.ResultsVIP 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.ConclusionsOur 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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| Keywords: | Apical lesions cytokines regulatory T cells T helper vasoactive intestinal peptide wound healing |
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