title: Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis.
abstract: In periodontitis, a common chronic inflammatory condition, gram-negative-rich bacterial biofilms trigger, in susceptible individuals, perpetuating inflammation that results in extensive tissue damage of tooth supporting structures. To delineate immune cell-dependent mechanisms whereby bacterial challenge drives persistent destructive inflammation in periodontitis and other inflammatory diseases, we studied involved tissues ex vivo and investigated host cell responses to the periodontal pathogen Porphyromonas gingivalis, in vitro. Diseased lesions were populated by abundant Th17 cells, linked to infection, chronic inflammation/autoimmunity and tissue pathology. In vitro, P. gingivalis, particularly the more virulent strain W83, stimulated myeloid antigen presenting cells (APC) to drive Th17 polarization. Supernatants from myeloid APC exposed to P. gingivalis were capable of enhancing Th17 but not Th1 polarization. P. gingivalis favored the generation of Th17 responses by stimulating the production of Th17 related cytokines IL-1β, IL-6 and IL-23, but not Th1 related IL-12. By inducing NFκB activation, P. gingivalis promoted IL-1β, IL-6 and IL-12p40 production, but not IRF3 phosphorylation, connected to generation of the IL-12p35 chain, ultimately restricting formation of the intact IL-12 molecule. Promotion of Th17 lineage responses was also aided by P. gingivalis proteases, which appeared to differentially degrade pivotal cytokines. In this regard, IL-12 was largely degraded by P. gingivalis, whereas IL-1β was more resistant to proteolysis. Our data unveil multiple pathways by which P. gingivalis may orchestrate chronic inflammation, providing insights into interventional strategies.
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4352, USA. nmoutsopoulos@dir.nidr.nih.gov
authors.forename: Niki M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.forename: Heather M
authors.initials: HM
authors.lastname: Kling
authors.forename: Nikola
authors.initials: N
authors.lastname: Angelov
authors.forename: Wenwen
authors.initials: W
authors.lastname: Jin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Palmer
authors.forename: Salvador
authors.initials: S
authors.lastname: Nares
authors.forename: Manuel
authors.initials: M
authors.lastname: Osorio
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
mesh_terms: D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000382:microbiology; D016866:Bacteroidaceae Infections / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D055113:Chronic Periodontitis / Q000276:immunology* / Q000382:microbiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism / Q000382:microbiology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D016966:Porphyromonas gingivalis / Q000276:immunology*; D059748:Proteolysis; D015398:Signal Transduction; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D016328:NF-kappa B