title: Characterization of the Protective Role of Regulatory T Cells in Experimental Periapical Lesion Development and Their Chemoattraction Manipulation as a Therapeutic Tool.
abstract: BACKGROUND
  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.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
authors.forename: Carolina Favaro
authors.initials: CF
authors.lastname: Francisconi
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
authors.forename: Andreia Espindola
authors.initials: AE
authors.lastname: Vieira
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
authors.forename: Claudia Cristina
authors.initials: CC
authors.lastname: Biguetti
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Glowacki
authors.affiliation: Universidade do Sagrado Coração (USC); Bauru, São Paulo, Brazil.
authors.forename: Ana Paula Favaro
authors.initials: AP
authors.lastname: Trombone
authors.affiliation: Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Letra
authors.affiliation: Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Renato
authors.initials: R
authors.lastname: Menezes Silva
authors.affiliation: 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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Sfeir
authors.affiliation: 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.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Little
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil. Electronic address: garletgp@usp.br.
authors.forename: Gustavo Pompermaier
authors.initials: GP
authors.lastname: Garlet
mesh_terms: D000818:Animals; D054422:Chemokine CCL22 / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010483:Periapical Diseases / Q000276:immunology* / Q000628:therapy*; D054398:Receptors, CCR4 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D054398:Receptors, CCR4
keywords: Apical lesions; T helper; cytokines; regulatory T cells; wound healing