Carolina Favaro Francisconi1, Andreia Espindola Vieira1, Claudia Cristina Biguetti1, Andrew J Glowacki2, Ana Paula Favaro Trombone3, Ariadne Letra4, Renato Menezes Silva4, Charles S Sfeir5, Steven R Little6, Gustavo Pompermaier Garlet7. 1. Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil. 2. Departments of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 3. Universidade do Sagrado Coração (USC); Bauru, São Paulo, Brazil. 4. Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas. 5. Department of Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Oral Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. 6. Departments of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania. 7. Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil. Electronic address: garletgp@usp.br.
Abstract
INTRODUCTION: The pathogenesis of periapical lesions is determined by the balance between host proinflammatory immune response and counteracting anti-inflammatory and reparative responses, which include regulatory T cells (Tregs) as potential immunoregulatory agents. In this study, we investigated (in a cause-and-effect manner) the involvement of CCL22-CCR4 axis in Treg migration to the periapical area and the role of Tregs in the determination of outcomes in periapical lesions. METHODS: Periapical lesions were induced in C57Bl/6 (wild-type) and CCR4KO mice (pulp exposure and bacterial inoculation) and treated with anti-glucocorticoid-induced TNF receptor family regulated gene to inhibit Treg function or alternatively with CCL22-releasing, polylactic-glycolic acid particles to induce site-specific migration of Tregs. After treatment, lesions were analyzed for Treg influx and phenotype, overall periapical bone loss, and inflammatory/immunologic and wound healing marker expression (analyzed by real-time polymerase chain reaction array). RESULTS: Treg inhibition by anti-glucocorticoid-induced TNF receptor family regulated gene or CCR4 depletion results in a significant increase in periapical lesion severity, associated with upregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with decreased Treg and healing marker expression. The local release of CCL22 in the root canal system resulted in the promotion of Treg migration in a CCR4-dependent manner, leading to the arrest of periapical lesion progression, associated with downregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with increased Treg and healing marker expression. CONCLUSIONS: Because the natural and CCL22-induced Treg migration switches active lesion into inactivity phenotype, Treg chemoattractant may be a promising strategy for the clinical management of periapical lesions.
INTRODUCTION: The pathogenesis of periapical lesions is determined by the balance between host proinflammatory immune response and counteracting anti-inflammatory and reparative responses, which include regulatory T cells (Tregs) as potential immunoregulatory agents. In this study, we investigated (in a cause-and-effect manner) the involvement of CCL22-CCR4 axis in Treg migration to the periapical area and the role of Tregs in the determination of outcomes in periapical lesions. METHODS: Periapical lesions were induced in C57Bl/6 (wild-type) and CCR4KO mice (pulp exposure and bacterial inoculation) and treated with anti-glucocorticoid-induced TNF receptor family regulated gene to inhibit Treg function or alternatively with CCL22-releasing, polylactic-glycolic acid particles to induce site-specific migration of Tregs. After treatment, lesions were analyzed for Treg influx and phenotype, overall periapical bone loss, and inflammatory/immunologic and wound healing marker expression (analyzed by real-time polymerase chain reaction array). RESULTS:Treg inhibition by anti-glucocorticoid-induced TNF receptor family regulated gene or CCR4 depletion results in a significant increase in periapical lesion severity, associated with upregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with decreased Treg and healing marker expression. The local release of CCL22 in the root canal system resulted in the promotion of Treg migration in a CCR4-dependent manner, leading to the arrest of periapical lesion progression, associated with downregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with increased Treg and healing marker expression. CONCLUSIONS: Because the natural and CCL22-induced Treg migration switches active lesion into inactivity phenotype, Treg chemoattractant may be a promising strategy for the clinical management of periapical lesions.
Authors: Gustavo Pompermaier Garlet; Richard Horwat; Herbert L Ray; Thiago Pompermaier Garlet; Elcia Maria Silveira; Ana Paula Campanelli; Ana Paula Favaro Trombone; Ariadne Letra; Renato Menezes Silva Journal: J Endod Date: 2011-10-27 Impact factor: 4.171
Authors: M Colić; D Gazivoda; D Vucević; I Majstorović; S Vasilijić; R Rudolf; Z Brkić; P Milosavljević Journal: J Dent Res Date: 2009-11 Impact factor: 6.116
Authors: Ana Claudia Araujo-Pires; Andreia Espindola Vieira; Carolina Favaro Francisconi; Claudia Cristina Biguetti; Andrew Glowacki; Sayuri Yoshizawa; Ana Paula Campanelli; Ana Paula Favaro Trombone; Charles S Sfeir; Steven R Little; Gustavo Pompermaier Garlet Journal: J Bone Miner Res Date: 2015-03 Impact factor: 6.741
Authors: Siddharth Jhunjhunwala; Giorgio Raimondi; Andrew J Glowacki; Sherri J Hall; Dan Maskarinec; Stephen H Thorne; Angus W Thomson; Steven R Little Journal: Adv Mater Date: 2012-07-23 Impact factor: 30.849
Authors: S Y Fukada; T A Silva; I F Saconato; G P Garlet; M J Avila-Campos; J S Silva; F Q Cunha Journal: J Dent Res Date: 2008-12 Impact factor: 6.116