title: Critical role of apoptotic speck protein containing a caspase recruitment domain (ASC) and NLRP3 in causing necrosis and ASC speck formation induced by Porphyromonas gingivalis in human cells.
abstract: Periodontal disease is a chronic inflammatory disorder that leads to the destruction of tooth-supporting tissue and affects 10-20 million people in the U.S. alone. The oral pathogen Porphyromonas gingivalis causes inflammatory host response leading to periodontal and other secondary inflammatory diseases. To identify molecular components that control host response to P. gingivalis in humans, roles for the NLR (NBD-LRR) protein, NLRP3 (cryopyrin, NALP3), and its adaptor apoptotic speck protein containing a C-terminal caspase recruitment domain (ASC) were studied. P. gingivalis strain A7436 induces cell death in THP1 monocytic cells and in human primary peripheral blood macrophages. This process is ASC and NLRP3 dependent and can be replicated by P. gingivalis LPS and Escherichia coli. P. gingivalis-induced cell death is caspase and IL-1 independent and exhibits morphological features consistent with necrosis including loss of membrane integrity and release of cellular content. Intriguingly, P. gingivalis-induced cell death is accompanied by the formation of ASC aggregation specks, a process not previously described during microbial infection. ASC specks are observed in P. gingivalis-infected primary human mononuclear cells and are dependent on NLRP3. This work shows that P. gingivalis causes ASC- and NLRP3-dependent necrosis, accompanied by ASC speck formation.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Max Tze-Han
authors.initials: MT
authors.lastname: Huang
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holley-Guthrie
authors.forename: Chris B
authors.initials: CB
authors.lastname: Moore
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.forename: Victoria
authors.initials: V
authors.lastname: Madden
authors.forename: Rebecca Keyser
authors.initials: RK
authors.lastname: Parsons
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Featherstone
authors.forename: Roland R
authors.initials: RR
authors.lastname: Arnold
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.forename: Jenny Pan-Yun
authors.initials: JP
authors.lastname: Ting
mesh_terms: D016866:Bacteroidaceae Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D046529:Microscopy, Electron, Transmission; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D016966:Porphyromonas gingivalis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human