Differential Immune Responses of 3D Gingival and Periodontal Connective Tissue Equivalents to Microbial Colonization

Overview

Journal J Tissue Eng

Date 2022 Aug 4

PMID 35923175

Authors

Hardik Makkar

Srividya Atkuru

Yi Ling Tang

Tanya Sethi

Chwee Teck Lim

Kai Soo Tan

Gopu Sriram

Affiliations

Soon will be listed here.

Abstract

Gingival and periodontal ligament fibroblasts are functionally distinct cell types within the dento-gingival unit that participate in host immune response. Their microenvironment influences the behavior and immune response to microbial challenge. We developed three-dimensional gingival and periodontal connective tissue equivalents (CTEs) using human fibrin-based matrix. The CTEs were characterized, and the heterogeneity in their innate immune response was investigated. The CTEs demonstrated no to minimal response to planktonic and , while their biofilms elicited a moderate increase in IL-6 and IL-8 production. In contrast, provoked a substantial increase in IL-6 and IL-8 production. Interestingly, the gingival CTEs secreted significantly higher IL-6, while periodontal counterparts produced higher IL-8. In conclusion, the gingival and periodontal CTEs exhibited differential responses to various bacterial challenges. This gives insights into the contribution of tissue topography and fibroblast heterogeneity in rendering protective and specific immune responses toward early biofilm colonizers.

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References

Han X, Amar S . Identification of genes differentially expressed in cultured human periodontal ligament fibroblasts vs. human gingival fibroblasts by DNA microarray analysis. J Dent Res. 2002; 81(6):399-405. DOI: 10.1177/154405910208100609. View

Scheibner K, Lutz M, Boodoo S, Fenton M, Powell J, Horton M . Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006; 177(2):1272-81. DOI: 10.4049/jimmunol.177.2.1272. View

Oberoi G, Janjic K, Muller A, Schadl B, Andrukhov O, Moritz A . Contraction Dynamics of Rod Microtissues of Gingiva-Derived and Periodontal Ligament-Derived Cells. Front Physiol. 2019; 9:1683. PMC: 6308197. DOI: 10.3389/fphys.2018.01683. View

Miller C, Septier D, Bonnefoix M, Lecolle S, Lebreton-Decoster C, Coulomb B . Human dermal and gingival fibroblasts in a three-dimensional culture: a comparative study on matrix remodeling. Clin Oral Investig. 2002; 6(1):39-50. DOI: 10.1007/s00784-001-0143-2. View

Uchida Y, Shiba H, Komatsuzawa H, Takemoto T, Sakata M, Fujita T . Expression of IL-1 beta and IL-8 by human gingival epithelial cells in response to Actinobacillus actinomycetemcomitans. Cytokine. 2001; 14(3):152-61. DOI: 10.1006/cyto.2001.0863. View

Nilsson B . Mechanisms involved in regulation of periodontal ligament cell production of pro-inflammatory cytokines: Implications in periodontitis. J Periodontal Res. 2020; 56(2):249-255. PMC: 7984126. DOI: 10.1111/jre.12823. View

Frevert C, Felgenhauer J, Wygrecka M, Nastase M, Schaefer L . Danger-Associated Molecular Patterns Derived From the Extracellular Matrix Provide Temporal Control of Innate Immunity. J Histochem Cytochem. 2018; 66(4):213-227. PMC: 5958376. DOI: 10.1369/0022155417740880. View

Hsieh J, Smith T, Meli V, Tran T, Botvinick E, Liu W . Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen. Acta Biomater. 2016; 47:14-24. PMC: 5426227. DOI: 10.1016/j.actbio.2016.09.024. View

Sriram G, Sudhaharan T, Wright G . Multiphoton Microscopy for Noninvasive and Label-Free Imaging of Human Skin and Oral Mucosa Equivalents. Methods Mol Biol. 2019; 2150:195-212. DOI: 10.1007/7651_2019_220. View

10.

Wang P, Fujii T, Kowashi Y, Kikuchi M, Suetsugu Y, Tanaka J . Heterogeneous expression of Toll-like receptor 4 and downregulation of Toll-like receptor 4 expression on human gingival fibroblasts by Porphyromonas gingivalis lipopolysaccharide. Biochem Biophys Res Commun. 2001; 288(4):863-7. DOI: 10.1006/bbrc.2001.5842. View

11.

McKnight H, Kelsey W, Hooper D, Hart T, Mariotti A . Proteomic analyses of human gingival and periodontal ligament fibroblasts. J Periodontol. 2013; 85(6):810-8. DOI: 10.1902/jop.2013.130161. View

12.

Wang P, Azuma Y, Shinohara M, Ohura K . Toll-like receptor 4-mediated signal pathway induced by Porphyromonas gingivalis lipopolysaccharide in human gingival fibroblasts. Biochem Biophys Res Commun. 2000; 273(3):1161-7. DOI: 10.1006/bbrc.2000.3060. View

13.

Pollanen M, Gursoy U, Kononen E, Uitto V . Fusobacterium nucleatum biofilm induces epithelial migration in an organotypic model of dento-gingival junction. J Periodontol. 2012; 83(10):1329-35. DOI: 10.1902/jop.2012.110535. View

14.

Souza P, Lundberg P, Lundgren I, Magalhaes F, Costa-Neto C, Lerner U . Activation of Toll-like receptor 2 induces B and B kinin receptors in human gingival fibroblasts and in mouse gingiva. Sci Rep. 2019; 9(1):2973. PMC: 6393418. DOI: 10.1038/s41598-018-37777-z. View

15.

Abranches J, Zeng L, Kajfasz J, Palmer S, Chakraborty B, Wen Z . Biology of Oral Streptococci. Microbiol Spectr. 2018; 6(5). PMC: 6287261. DOI: 10.1128/microbiolspec.GPP3-0042-2018. View

16.

Garcia-Garcia A, Martin I . Extracellular Matrices to Modulate the Innate Immune Response and Enhance Bone Healing. Front Immunol. 2019; 10:2256. PMC: 6764079. DOI: 10.3389/fimmu.2019.02256. View

17.

Kurgan S, Kantarci A . Molecular basis for immunohistochemical and inflammatory changes during progression of gingivitis to periodontitis. Periodontol 2000. 2017; 76(1):51-67. DOI: 10.1111/prd.12146. View

18.

Rowley A, Nagalla R, Wang S, Liu W . Extracellular Matrix-Based Strategies for Immunomodulatory Biomaterials Engineering. Adv Healthc Mater. 2019; 8(8):e1801578. PMC: 7568845. DOI: 10.1002/adhm.201801578. View

19.

Klanliang K, Asahi Y, Maezono H, Sotozono M, Kuriki N, Machi H . An extensive description of the microbiological effects of silver diamine fluoride on dental biofilms using an oral in situ model. Sci Rep. 2022; 12(1):7435. PMC: 9076617. DOI: 10.1038/s41598-022-11477-1. View

20.

Kang W, Hu Z, Ge S . Healthy and Inflamed Gingival Fibroblasts Differ in Their Inflammatory Response to Porphyromonas gingivalis Lipopolysaccharide. Inflammation. 2016; 39(5):1842-52. DOI: 10.1007/s10753-016-0421-4. View