title: A Dual Role for P2X7 Receptor during Porphyromonas gingivalis Infection.
abstract: Emerging evidence suggests a role for purinergic signaling in the activation of multiprotein intracellular complexes called inflammasomes, which control the release of potent inflammatory cytokines, such as interleukin (IL) -1β and -18. Porphyromonas gingivalis is intimately associated with periodontitis and is currently considered one of the pathogens that can subvert the immune system by limiting the activation of the NLRP3 inflammasome. We recently showed that P. gingivalis can dampen eATP-induced IL-1β secretion by means of its fimbriae in a purinergic P2X7 receptor-dependent manner. Here, we further explore the role of this purinergic receptor during eATP-induced IL-1β processing and secretion by P. gingivalis-infected macrophages. We found that NLRP3 was necessary for eATP-induced IL-1β secretion as well as for caspase 1 activation irrespective of P. gingivalis fimbriae. Additionally, although the secretion of IL-1β from P. gingivalis-infected macrophages was dependent on NLRP3, its adaptor protein ASC, or caspase 1, the cleavage of intracellular pro-IL-1β to the mature form was found to occur independently of NLRP3, its adaptor protein ASC, or caspase 1. Our in vitro findings revealed that P2X7 receptor has a dual role, being critical not only for eATP-induced IL-1β secretion but also for intracellular pro-IL-1β processing. These results were relevant in vivo since P2X7 receptor expression was upregulated in a P. gingivalis oral infection model, and reduced IFN-γ and IL-17 were detected in draining lymph node cells from P2rx7(-/-) mice. Furthermore, we demonstrated that P2X7 receptor and NLRP3 transcription were modulated in human chronic periodontitis. Overall, we conclude that the P2X7 receptor has a role in periodontal immunopathogenesis and suggest that targeting of the P2X7/NLRP3 pathway should be considered in future therapeutic interventions in periodontitis.
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: E S
authors.initials: ES
authors.lastname: Ramos-Junior
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Morandini
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: C L C
authors.initials: CL
authors.lastname: Almeida-da-Silva
authors.affiliation: Department of Periodontology, School of Dentistry, Catholic University of Brasília, Brasília, Brazil.
authors.forename: E J
authors.initials: EJ
authors.lastname: Franco
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, USA; and Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Potempa
authors.affiliation: Faculty of Dentistry, University of Sydney, Sydney, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Nguyen
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Oliveira
authors.affiliation: Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: D S
authors.initials: DS
authors.lastname: Zamboni
authors.affiliation: Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ojcius
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Scharfstein
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil rcsilva@biof.ufrj.br.
authors.forename: R
authors.initials: R
authors.lastname: Coutinho-Silva
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000378:metabolism* / Q000382:microbiology; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016966:Porphyromonas gingivalis / Q000472:pathogenicity*; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1
keywords: ATP; IL-1β; cytokines; inflammasome; macrophage; periodontitis