Role of macrophage polarization towards M1 profile in the alveolar bone repair and osseointegration processes in mice

• Grant number: 18/25708-0
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2019
• Effective date (End): November 30, 2021
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Gustavo Pompermaier Garlet
• Grantee: André Petenuci Tabanez
• Home Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated research grant: 15/24637-3 - MSCs and m2 as determinants of the constructive or destructive nature of inflammatory microenvironments associated with bone tissue, AP.TEM

Abstract

Bone tissue is a mineralized tissue, characterized by its plasticity, derived from the remodeling process, in which bone resorption followed by neoformation occurs coordinated through a dynamic balance of osteoblast and osteoclast activity, as well as high tissue repair capacity. Recently, the study of the interaction between the immune and skeletal systems has received special attention in a recent research section called osteoimmunology. In this context, the polarization of macrophages in M1/M2 profiles has been shown to be an important event for the immunoregulation of both pathological processes and tissue repair processes. A recent study by our research group demonstrated a transition in macrophage polarization throughout the repair process, with initial domain M1 followed temporally by the M2 cell domain, as well as demonstrating that macrophage polarization potentiation to an M2 profile through of the administration of FTY720 improves alveolar bone repair in C57BI/6 mice. Results of an osseointegration model also suggest that the M1/M2 transition is associated with adequate osseointegration of Ti devices implanted in the maxilla of mice. These results suggest macrophages with the M1 and M2 phenotypes, actively participate in the initial and final stages of the repair respectively, contributing to the induction and resolution of inflammation and promoting tissue repair. However, the real role of the M1/M2 polarization in the bone repair process, and in the process of osseointegration, remain unknown. M1 macrophages contribute to the early 'constructive inflammation' process, which enables cell migration to the repair site. In fact, the onset of the repair process is marked by the presence of inflammatory mediators such as IL-6, IL-1, TNF-±, which act by recruiting inflammatory cells to the lesion site, and at that early stage the population of macrophages present at the site of the lesion predominantly presents the proinflammatory phenotype or M1. In this context, it is important to mention that one of the factors potentially related to the reduction of the tissue repair capacity associated to the aging process concerns the limited capacity of M1 response described in elderly individuals, reinforcing the potential importance of M1 cells as a 'trigger' of the repair process. However, both the intensity of such inflammatory process, as well as its cellular and molecular nature, remain unknown as well as the influence of M1/M2 polarization in determining the constructive or destructive nature of inflammatory microenvironments associated with bone tissue. In this context, considering the scarcity of information in the literature regarding the M1/M2 polarization in bone tissue repair and osseointegration, we will use as an experimental strategy the induction of M1 polarization, which indirectly tends to change the balance and kinetic M1/M2, of in order to determine the impact of M1 macrophages and M1/M2 balance using alveolar bone repair models and intra oral implant models in C57Bl/6 mice previously developed and characterized by our group. Considering that polarization of macrophages to the M1 pattern occurs at the response site after migration, we will treat the animals with Paclitaxel, a drug that induces M1 polarization, in order to direct the development of such a response; thus determining the impact of M1 responses on local immunoregulation and on alveolar bone repair and osseointegration. Additionally, we will analyze the role of M1 polarization in elderly mice, characterized by both limited repair capacity and M1 response deficiency, as an alternative potential to potentiate repair in such conditions. (AU)