The role of VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) in M2 polarization and the impact on the alveolar bone healing process

Author(s)

Michelle de Campos Soriani Azevedo

• Document type: Doctoral Thesis
• Press: Bauru.
• Institution: Universidade de São Paulo (USP). Faculdade de Odontologia de Bauru (FOB/SDB)
• Defense date: 2019-10-25

Examining board members

Gustavo Pompermaier Garlet; Leonardo Rigoldi Bonjardim; Luciana Raquel Vincenzi Fachin; Gabriela Gennaro

• Advisor: Gustavo Pompermaier Garlet

Abstract

This study evaluated the role of VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase activating polypeptide) in modulating immune and inflammatory response associated with bone tissue using alveolar bone repair models and periapical lesions in C57Bl/6 mice. Regarding repair, groups submitted to extraction, maintained under control or treated with VIP, antiVIP, PACAP and antiPACAP were evaluated by microtomography (CT), histomorphometric, immunohistochemical and molecular analysis. The CT results showed no difference between VIP and antiVIP groups in relation to control, whereas histomorphometric analyzes showed lower connective tissue density in antiVIP group, as well as lower density of collagen fibers and fibroblasts associated with higher bone matrix and osteoclasts density in the VIP and antiVIP groups; associated with a lower F4/80+, CD80+, VIP+ and PACAP+, increased CD206+ cell count, changing the expression of growth factors, immunological and tissue repair markers. In the PACAP and antiPACAP-treated groups, CT analysis showed increased bone volume for PACAP and trabecular thickness in the PACAP and antiPACAP groups, while histomorphometric analysis showed increased collagen fibers and fibroblasts and decreased in the density of osteoblasts and osteoclasts in the PACAP group. The antiPACAP group showed decreased osteoblasts and higher concentration of inflammatory cells. Immunohistochemical analysis showed that the PACAP and antiPACAP groups in general had lower F4/80+, CD80+, VIP+ and PACAP+ and an increase in CD206+ cell counts, followed by altered expression of growth factors, immune and repair markers. In general, it was observed that administration of VIP and PACAP resulted in a faster repair process with higher bone density at the end of the period, associated with a preferential polarization of response to the M2 profile. Regarding the chronic inflammatory osteolysis model, mice submitted to induction of periapical lesions, maintained under control conditions or treated with VIP, were evaluated by histomorphometric, cellular and molecular analyzes. VIP expression was higher in periapical granulomas, presenting a positive association with immunoregulatory factors and inverse correlation with pro-inflammatory mediators. Treatment with VIP resulted in lesion control associated with an anti-inflammatory response related to Th1, Th17 and osteoclastogenic responses, which was dependent on Treg migration and independent of IL-4. Thus our results show that VIP and/or PACAP are associated with anti-inflammatory activity and that treatments result in attenuation of lesion progression and improved bone repair process associated with an immunosuppressive response. In general, it can be concluded that neuropeptides, such as VIP and PACAP, have a regulatory action on immune and inflammatory response associated with bone tissue, and that the magnitude of such regulation seems to be dependent on the nature of the inflammatory process. (AU)

• FAPESP's process: 15/25618-2 - VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) roles in M2 polarization and their impact on the alveolar bone repair process
• Grantee: Michelle de Campos Soriani Azevedo
• Support Opportunities: Scholarships in Brazil - Doctorate