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Signaling by purinergic receptor P2X7 and histone deacetylases in the innate immune response of human periodontal fibroblasts: implications in the pathogenesis of periodontitis

Grant number: 13/16113-9
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2014
Effective date (End): May 31, 2016
Field of knowledge:Health Sciences - Dentistry - Periodontology
Principal Investigator:Carlos Ferreira dos Santos
Grantee:Ana Carolina Morandini Ramos
Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
Associated scholarship(s):15/20954-4 - The role of Porphyromonas gingivalis-Nucleoside diphosphate kinase in epigenetic modulation of P2X7 receptor, BE.EP.PD


Fibroblasts are now seen as active components of the immune response because these cells express Toll-like receptors (TLRs), recognize pathogen-associated molecular patterns, and mediate the production of cytokines and chemokines during inflammation. The molecular mechanisms that contribute to the inflammatory response mediated by fibroblastic cells, in a differential manner depending on their origin, remain unclear, since the regulatory machinery of inflammation is remarkably complex. It is known that P. gingivalis induces the secretion of IL-1² through still poorly understood mechanisms involving extracellular ATP and the purinergic receptor P2X7. Preliminary data from our group have shown that P2X7 mRNA is differently expressed by human gingival fibroblasts as compared to the periodontal ligament cells from the same donor. Preliminary evidence also shows an increased expression of P2X7 receptor in an experimental animal model of periodontal disease induction, demonstrating the involvement of this receptor in the pathogenesis of periodontitis. The literature also reports that the regulation of pro-inflammatory cytokines production can be influenced by several mechanisms, among which the regulation of histone acetylation by histone deacetylase enzymes (HDACs). Therefore, this study aims to investigate the involvement of purinergic signaling in periodontitis and how this signaling may be regulated by epigenetic mechanisms, such as modulation of inflammatory mediators' expression by regulating the expression and activity of HDACs in the context of periodontitis pathogenesis. For this purpose, primary human fibroblasts derived from periodontal ligament and gingiva of healthy and chronic periodontitis donors will be evaluated for gene and protein expression of P2X7 and HDACs, as well as their influence on the modulation of chemokine and cytokine expression when stimulated by P. gingivalis LPS. mRNA expression of P2X7, HDACs and cytokines /chemokines will be evaluated by RT-qPCR and proteins by ELISA or Western blotting. Immunofluorescence will also be used to confirm the findings of protein expression and any comparisons of differences between experimental groups. The HDAC enzyme activity will be detected by colorimetric assay.

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Scientific publications
(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)
MORANDINI, ANA CAROLINA; SANTOS, CARLOS F.; YILMAZ, OEZLEM. Role of epigenetics in modulation of immune response at the junction of host-pathogen interaction and danger molecule signaling. PATHOGENS AND DISEASE, v. 74, n. 7, . (13/16113-9, 15/20954-4)
GABRIELE, LILIAN GOBBO; MORANDINI, ANA CAROLINA; DIONISIO, THIAGO JOSE; SANTOS, CARLOS FERREIRA. Angiotensin II Type 1 Receptor Knockdown Impairs Interleukin-1 beta-Induced Cytokines in Human Periodontal Fibroblasts. Journal of Periodontology, v. 88, n. 1, p. E1-E11, . (13/16113-9, 15/03965-2, 15/20954-4)
SANTOS, CARLOS F.; MORANDINI, ANA C.; DIONISIO, THIAGO J.; FARIA, FLAVIO A.; LIMA, MARTA C.; FIGUEIREDO, CAIO M.; COLOMBINI-ISHIKIRIAMA, BELLA L.; SIPERT, CARLA R.; MACIEL, RUBENS P.; AKASHI, ANA P.; et al. Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue. PLoS One, v. 10, n. 8, . (13/16113-9, 05/60167-0, 09/53848-1, 09/15372-5, 10/01230-1)

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