Role of genotypes selected for minimum and maximum inflammatory reactivity in the response to biomaterials (Ti) grafting and in the subsequent osseointegration process in mice

Abstract

Studies suggest that the inflammatory immune response, since presenting a profile of controlled and self-limited nature, is important in the repair and osseointegration process, contributing possibly as a mediator of the chemoattraction, activation and differentiation of several cell types involved in the repair. Among the different cell types recruited during the response, macrophages are also considered as important elements in the repair and osseointegration process. Although classically considered as proinflammatory cells, macrophages may present distinct functional phenotypes, called M1 (considered pro-inflammatory) and M2 (anti-inflammatory and/or pro-reparative). As for tissue repair, M1 macrophages are believed to predominate in the early stages and contribute to the early 'constructive inflammation' process, which enables cell migration to the repair site, helping to remove necrotic/damaged tissues, followed by the transition for the subsequent predominance of M2 cells, which would constitute an important source of growth factors in the repair site. On the contrary, chronic and exacerbated responses, characterized by a lack of control of the balance between pro-and anti-inflammatory mediators, in theory have a deleterious effect on the repair and osseointegration process. In this context, the use of mouse strains with different inflammatory phenotypes has proved to be an extremely useful experimental tool in the study of the influence of the immune and inflammatory response in different models. Genetically selected strains of mice for maximal or minimal inflammatory response were developed through two-way selective breeding, giving rise to AIRmax and AIRmin lines; thus denominated by its Acute Inflammatory Reaction (AIR), maximum (max) or minimum (min). The gene SLc11a1 was identified as one of the responsible for the differential response of these lines, responding to AIRmax hyperresponsiveness (R allele) and low responsiveness of AIRmin (S allele). Although the exact mechanisms by which Slc11a1 regulates the inflammatory immune response remain poorly understood, studies suggest that its action is derived from the control regulation of the flow of Fe ions, which in turn modulate macrophage function/polarization. Considering the scarcity of information in the literature regarding the influence of the immune and inflammatory response on the osseointegration/ repair process associated to biomaterials, this project aims to determine the characteristics of the immune/inflammatory response of mice of the AIRmin and AIRmax lines subsequent to the implantation of (Ti screw in the maxilla, osseointegration model, Ti disk in the subcutaneous tissue, model of immune/inflammatory response and repair), and its impact on the process of osseointegration/repair. After characterization of the response and osseointegration / repair phenotypes of the AIRmin and AIRmax lines and the characterization of the inflammatory immune response (with a main focus on the M1/M2 polarization), we will use polarization targeting strategies for reversion of the unfavorable phenotype and potentialization of the favorable phenotype, seeking the potential of osseointegration. Specifically, we will use the AIRmin and AIRmax strains in the models of osseointegration (Ti bolt implantation in the maxilla) and immune/inflammatory response and repair (Ti disk implantation in the subcutaneous tissue), such models being evaluated through microtomography, histological analyzes (histomorphometry, immunohistochemistry and birefringence analysis), as well as molecular analysis by means of PCR Array, to be validated by ELISA. It is believed that the joint analysis will contribute to the clarification of the magnitude and nature of the immune/inflammatory process and the response to biomaterials, and their impact on subsequent osseointegration and repair processes. (AU)