MSCs and m2 as determinants of the constructive or destructive nature of inflammatory microenvironments associated with bone tissue

• Grant number: 15/24637-3
• Support Opportunities: Research Projects - Thematic Grants
• Duration: June 01, 2016 - May 31, 2023
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Gustavo Pompermaier Garlet
• Grantee: Gustavo Pompermaier Garlet
• Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated researchers: Camila de Oliveira Rodini Pegoraro ; Chales Sfeir ; Danieli Balbueno Contreira Rodrigues ; Fred Kurtis Kasper ; Marcelo de Franco ; Renato Menezes Silva ; Rodrigo Cardoso de Oliveira ; Tarcília Aparecida da Silva
• Associated scholarship(s): 19/12120-7 - 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, BP.DR; 18/25708-0 - Role of macrophage polarization towards M1 profile in the alveolar bone repair and osseointegration processes in mice, BP.DR; 19/01214-0 - Role of macrophage polarization for an M2 profile in the response to the implantation of classical biomaterials (Ti) and its impact on the repair and osseointegration processes., BP.PD; 18/10177-9 - Analysis of MEK1/2 and STAT6 impact on macrophage polarization to M2 phenotype, and its influence on the alveolar repair process in mice., BP.DR; 18/08741-3 - ROLE OF MSCs IN THE RESPONSE TO THE IMPLANTATION OF TITANIUM DEVICES AND ITS IMPACT ON THE REPAIR AND OSSEOINTEGRATION PROCESS, BP.PD

Abstract

Variations in the nature of inflammatory immune response, which include variations in its intensity, extent and the involvement of different cellular subsets and the polarization of immune response, allow the conclusion that the interaction of inflammatory immune response with bone tissue can result in destructive or constructive outcomes. While the destructive responses nature is relatively well known in the view of the extensive studies focused in chronic osteolytic inflammatory conditions, studies with specific focus in the constructive features of inflammation in tissue repair are more recent and less numerous. In the destructive inflammation context, pro-inflammatory and Th1- and Th17-type cytokines are associated with the progression of osteolytic lesions, such as periodontal and periapical lesions. On the other hand, our research group described a protective role for Tregs (regulatory T cells) as determinants of periodontal and periapical lesions inactivity, associated with a drastic change in the local inflammatory microenvironment. However, preliminary results demonstrate that Tregs migration and action does not take place as an alienated event, being other cell types potentially involved in the determination of a constructive and pro-reparative nature of the inflammatory environment. Indeed, inactive periapical lesions are also characterized by the marked immunoregulatory and potentially reparative activity of mesenchymal stem cells (MSCs), as well by the dominance of macrophages presenting a M2 phenotype. Therefore, the immunoregulatory events attributed to Tregs can involve as mediators or boosters, MSCs and M2, which can act independently or a cooperative manner. In this context, it is important to consider that inactive lesions are characterized by the increased expression of healing markers, demonstrating that even in chronic inflammatory processes, variations in the patterns of inflammatory immune response can mediate (at least partially) the attempt of repair, supporting the possible constructive nature of some inflammatory processes. Accordingly, both MSCs and M2 are considered as key cell types in the tissue healing process, as well studies suggest its contribution as determinants of a successful clinical outcome of biomaterial grafting. However, despite such hypothesis, the immunoregulatory and reparative role of M2 and MCSs in the bone healing (associated or with biomaterials, such as Ti), remains to be definitely confirmed by cause-and-effect experiments; as well its potential protective role in destructive chronic inflammatory reactions associated with bone resorption. Therefore, this project has as general objective the study of the determinants of constructive or destructive nature of inflammatory immune response associated with bone tissue, with specific focus in the migration and function of MSCs and M2, in its potential regulation by Tregs; as well in the possible influence of biomaterials in the course of the inflammatory response and the consequent impact in the success of failure of its application. To accomplish such objectives, we will conduct in vivo experiments with genetically modified mice, as well experiments with pharmacological inhibition or induction of specific targets and in vitro experiments, which will allow the establishment of cause-and-effect relation between the migration, polarization and action of specific cell types, unraveling the mechanisms underlying the determinants of the constructive or destructive nature of inflammatory microenvironments, with potential application towards the development of translational strategies to the modulation of inflammation in clinical settings. (AU)

Scientific publications

(15)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CAVALLA, F.; LETRA, A.; SILVA, R. M.; GARLET, G. P.. Determinants of Periodontal/Periapical Lesion Stability and Progression. JOURNAL OF DENTAL RESEARCH, v. 100, n. 1, AUG 2020. (15/24637-3)

COLAVITE, PRISCILA MARIA; CAVALLA, FRANCO; GARLET, THIAGO POMPERMAIER; SORIANI AZEVEDO, MICHELLE DE CAMPOS; MELCHIADES, JESSICA LIMA; CAMPANELLI, ANA PAULA; LETRA, ARIADNE; FAVARO TROMBONE, ANA PAULA; SILVA, RENATO MENEZES; GARLET, GUSTAVO POMPERMAIER. TBX21-1993T/C polymorphism association with Th1 and Th17 response at periapex and with periapical lesions development risk. Journal of Leukocyte Biology, v. 105, n. 3, p. 609-619, MAR 2019. (14/03276-0, 15/18163-9, 15/24637-3, 14/17886-4)

CLAUDIA CRISTINA BIGUETTI; FRANCO CAVALLA; ELCIA M. SILVEIRA; ANGÉLICA CRISTINA FONSECA; ANDREIA ESPINDOLA VIEIRA; ANDRE PETENUCI TABANEZ; DANIELI C. RODRIGUES; ANA PAULA FAVARO TROMBONE; GUSTAVO POMPERMAIER GARLET. Oral implant osseointegration model in C57Bl/6 mice: microtomographic, histological, histomorphometric and molecular characterization. Journal of Applied Oral Science, v. 26, 2018-06-11. (14/09590-8, 15/24637-3, 15/18162-2)

BIGUETTI, CLAUDIA CRISTINA; VIEIRA, ANDREIA ESPINDOLA; CAVALLA, FRANCO; FONSECA, ANGELICA CRISTINA; COLAVITE, PRISCILA MARIA; SILVA, RENATO MENEZES; FAVARO TROMBONE, ANA PAULA; GARLET, GUSTAVO POMPERMAIER. CCR2 Contributes to F4/80+Cells Migration Along Intramembranous Bone Healing in Maxilla, but Its Deficiency Does Not Critically Affect the Healing Outcome. FRONTIERS IN IMMUNOLOGY, v. 9, AUG 10 2018. (12/03636-0, 15/24637-3)

COLAVITE, PRISCILA MARIA; VIEIRA, ANDREIA ESPINDOLA; PALANCH REPEKE, CARLOS EDUARDO; DE ARAUJO LINHARI, RAFAELLA PAVANELLI; CARNEIRO SPERA DE ANDRADE, RAISSA GONSALVES; BORREGO, ANDREA; DE FRANCO, MARCELO; TROMBONE, ANA PAULA FAVARO; GARLET, GUSTAVO POMPERMAIER. Alveolar bone healing in mice genetically selected in the maximum (AIRmax) or minimum (AIRmin) inflammatory reaction. CYTOKINE, v. 114, p. 47-60, FEB 2019. (13/25824-6, 15/24637-3)

BIGUETTI, CLAUDIA CRISTINA; CAVALLA, FRANCO; FONSECA, ANGELICA CRISTINA; TABANEZ, ANDRE PETENUCCI; SIDDIQUI, DANYAL A.; WHEELIS, SUTTON E.; TAGA, RUMIO; FAKHOURI, WALID D.; SILVA, RENATO MENEZES; RODRIGUES, DANIELI C.; et al. Effects of Titanium Corrosion Products on In Vivo Biological Response: A Basis for the Understanding of Osseointegration Failures Mechanisms. FRONTIERS IN MATERIALS, v. 8, MAY 14 2021. (15/24637-3, 14/09590-8, 15/18162-2)

TABANEZ, ANDRE PETENUCI; SORIANI AZEVEDO, MICHELLE DE CAMPOS; MELCHIADES, JESSICA LIMA; FONSECA, ANGELICA CRISTINA; FRANCISCONI, CAROLINA FAVARO; COLAVITE, PRISCILA MARIA; BIGUETTI, CLAUDIA CRISTINA; RODINI PEGORARO, CAMILA DE OLIVEIRA; FAVARO TROMBONE, ANA PAULA; GARLET, GUSTAVO POMPERMAIER. FTY720 administration results in a M2 associated immunoregulatory effect that positively influences the outcome of alveolar bone repair outcome in mice. BONE, v. 163, p. 14-pg., 2022-07-28. (15/24637-3)

GARLET, G. P.; GIANNOBILE, W. V.. Macrophages: The Bridge between Inflammation Resolution and Tissue Repair?. JOURNAL OF DENTAL RESEARCH, v. 97, n. 10, p. 3-pg., 2018-09-01. (15/24637-3)

SORIANI AZEVEDO, MICHELLE DE CAMPOS; GARLET, THIAGO POMPERMAIER; FRANCISCONI, CAROLINA FAVARO; COLAVITE, PRISCILA MARIA; TABANEZ, ANDRE PETENUCI; MELCHIADES, JESSICA LIMA; FAVARO TROMBONE, ANA PAULA; SFEIR, CHARLES; LITTLE, STEVEN; SILVA, RENATO MENEZES; et al. Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions. JOURNAL OF ENDODONTICS, v. 45, n. 10, p. 1228-1236, OCT 2019. (15/25618-2, 15/24637-3)

FRANCISCONI, C. F.; VIEIRA, A. E.; AZEVEDO, M. C. S.; TABANEZ, A. P.; FONSECA, A. C.; TROMBONE, A. P. F.; LETRA, A.; SILVA, R. M.; SFEIR, C. S.; LITTLE, S. R.; et al. RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis. JOURNAL OF DENTAL RESEARCH, v. 97, n. 8, p. 917-927, JUL 2018. (13/05994-4, 12/15133-3, 15/24637-3)

BIGUETTI, CLAUDIA CRISTINA; CAVALLA, FRANCO; SILVEIRA, ELCIA VARIZE; TABANEZ, ANDRE PETENUCI; FRANCISCONI, CAROLINA FAVARO; TAGA, RUMIO; CAMPANELLII, ANA PAULA; TROMBONE, ANA PAULA FAVARO; RODRIGUES, DANIELI C.; GARLET, GUSTAVO POMPERMAIER. HGMB1 and RAGE as Essential Components of Ti Osseointegration Process in Mice. FRONTIERS IN IMMUNOLOGY, v. 10, APR 5 2019. (14/09590-8, 15/18162-2, 15/24637-3)

FRANCISCONI, CAROLINA FAVARO; COLAVITE, PRISCILA MARIA; FONSECA, ANGELICA CRISTINA; AZEVEDO, MICHELLE DE CAMPOS SORIANI; TABANEZ, ANDRE PETENUCI; MELCHIADES, JESSICA LIMA; VIEIRA, ANDREIA ESPINDOLA; REPEKE, CARLOS EDUARDO PALANCH; CLAUDINO, MARCELA; GARLET, GUSTAVO POMPERMAIER. Microtomographic, histomorphometric, and molecular features show a normal alveolar bone healing process in iNOS-deficient mice along a compensatory upregulation of eNOS and nNOS isoforms. Journal of Applied Oral Science, v. 31, p. 12-pg., 2023-01-01. (10/13626-7, 18/08741-3, 15/24637-3)

FONSECA, ANGELICA CRISTINA; MELCHIADES, JESSICA LIMA; SORIANI AZEVEDO, MICHELLE DE CAMPOS; COLAVITE, PRISCILA MARIA; FRANCISCONI MORTARI, CAROLINA FAVARO; TAMPANEZ, ANDRE PETENUCI; GARLET, GUSTAVO POMPERMAIER. MEK1/2 blockade results in altered inflammatory response and delayed alveolar bone repair. JOURNAL OF IMMUNOLOGY, v. 204, n. 1, p. 2-pg., 2020-05-01. (18/10177-9, 15/24637-3)

MELCHIADES, JESSICA LIMA; FRANCO CAVALLA, IAN; COLAVITE, PRISCILA MARIA; SORIANI AZEVEDO, MICHELLE DE CAMPOS; FONSECA, ANGELICA CRISTINA; FAVARO TROMBONE, ANA PAULA; DA SILVA, RENATO MENEZES; DE FAVERI, MARCELO; FIGUEIREDO, MAGDA FEREZ; GARLET, GUSTAVO P.. Slc11a1 gene variants influence over host response patterns and periodontal diseases resistance and susceptibility phenotypes. JOURNAL OF IMMUNOLOGY, v. 204, n. 1, p. 2-pg., 2020-05-01. (19/12120-7, 15/24637-3)

DE SOUZA, LETICIA CHAVES; CAVALLA, FRANCO; MAILI, LORENA; GARLET, GUSTAVO P.; VIEIRA, ALEXANDRE R.; SILVA, RENATO M.; LETRA, ARIADNE. WNT gene polymorphisms and predisposition to apical periodontitis. SCIENTIFIC REPORTS, v. 9, DEC 12 2019. (14/03276-0, 15/24637-3)