title: Stimulation of oral fibroblast chemokine receptors identifies CCR3 and CCR4 as potential wound healing targets.
abstract: The focus of this study was to determine which chemokine receptors are present on oral fibroblasts and whether these receptors influence proliferation, migration, and/or the release of wound healing mediators. This information may provide insight into the superior wound healing characteristics of the oral mucosa. The gingiva fibroblasts expressed 12 different chemokine receptors (CCR3, CCR4, CCR6, CCR9, CCR10, CXCR1, CXCR2, CXCR4, CXCR5, CXCR7, CX3CR1, and XCR1), as analyzed by flow cytometry. Fourteen corresponding chemokines (CCL5, CCL15, CCL20, CCL22, CCL25, CCL27, CCL28, CXCL1, CXCL8, CXCL11, CXCL12, CXCL13, CX3CL1, and XCL1) were used to study the activation of these receptors on gingiva fibroblasts. Twelve of these fourteen chemokines stimulated gingiva fibroblast migration (all except for CXCL8 and CXCL12). Five of the chemokines stimulated proliferation (CCL5/CCR3, CCL15/CCR3, CCL22/CCR4, CCL28/CCR3/CCR10, and XCL1/XCR1). Furthermore, CCL28/CCR3/CCR10 and CCL22/CCR4 stimulation increased IL-6 secretion and CCL28/CCR3/CCR10 together with CCL27/CCR10 upregulated HGF secretion. Moreover, TIMP-1 secretion was reduced by CCL15/CCR3. In conclusion, this in-vitro study identifies chemokine receptor-ligand pairs which may be used in future targeted wound healing strategies. In particular, we identified the chemokine receptors CCR3 and CCR4, and the mucosa specific chemokine CCL28, as having an predominant role in oral wound healing by increasing human gingiva fibroblast proliferation, migration, and the secretion of IL-6 and HGF and reducing the secretion of TIMP-1.
authors.affiliation: Department of Oral Cell Biology, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jeroen K
authors.initials: JK
authors.lastname: Buskermolen
authors.affiliation: Department of Oral Cell Biology, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Roffel
authors.affiliation: Department of Oral Cell Biology, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.|Department of Dermatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Susan
authors.identifier: http://orcid.org/0000-0002-3446-6138
authors.initials: S
authors.lastname: Gibbs
mesh_terms: D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019742:Chemokines, CC / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005881:Gingiva / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D054397:Receptors, CCR3 / Q000819:agonists* / Q000378:metabolism; D054398:Receptors, CCR4 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C414047:CCL28 protein, human; C515350:CCR3 protein, human; C515354:CCR4 protein, human; D019742:Chemokines, CC; C066855:HGF protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008024:Ligands; D054397:Receptors, CCR3; D054398:Receptors, CCR4; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D017228:Hepatocyte Growth Factor
keywords: chemokine; cytokine; gingiva; migration; proliferation