title: Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis.
abstract: The interleukin (IL)-1β-processing inflammasome has recently been identified as a target for pathogenic evasion of the inflammatory response by a number of bacteria and viruses. We postulated that the periodontal pathogen, Porphyromonas gingivalis may suppress the inflammasome as a mechanism for its low immunogenicity and pathogenic synergy with other, more highly immunogenic periodontal bacteria. Our results show that P. gingivalis lacks signaling capability for the activation of the inflammasome in mouse macrophages. Furthermore, P. gingivalis can suppress inflammasome activation by another periodontal bacterium, Fusobacterium nucleatum. This repression affects IL-1β processing, as well as other inflammasome-mediated processes, including IL-18 processing and cell death, in both human and mouse macrophages. F. nucleatum activates IL-1β processing through the Nlrp3 inflammasome; however, P. gingivalis repression is not mediated through reduced levels of inflammasome components. P. gingivalis can repress Nlrp3 inflammasome activation by Escherichia coli, and by danger-associated molecular patterns and pattern-associated molecular patterns that mediate activation through endocytosis. However, P. gingivalis does not suppress Nlrp3 inflammasome activation by ATP or nigericin. This suggests that P. gingivalis may preferentially suppress endocytic pathways toward inflammasome activation. To directly test whether P. gingivalis infection affects endocytosis, we assessed the uptake of fluorescent particles in the presence or absence of P. gingivalis. Our results show that P. gingivalis limits both the number of cells taking up beads and the number of beads taken up for bead-positive cells. These results provide a novel mechanism of pathogen-mediated inflammasome inhibition through the suppression of endocytosis.
authors: Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA. debra_taxman@med.unc.edu
authors: Debra J
authors: DJ
authors: Taxman
authors: Karen V
authors: KV
authors: Swanson
authors: Peter M
authors: PM
authors: Broglie
authors: Haitao
authors: H
authors: Wen
authors: Elizabeth
authors: E
authors: Holley-Guthrie
authors: Max Tze-Han
authors: MT
authors: Huang
authors: Justin B
authors: JB
authors: Callaway
authors: Tim K
authors: TK
authors: Eitas
authors: Joseph A
authors: JA
authors: Duncan
authors: Jenny P Y
authors: JP
authors: Ting
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004705:Endocytosis / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D005673:Fusobacterium / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016966:Porphyromonas gingivalis / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse