title: Porphyromonas gingivalis regulates TREM-1 in human polymorphonuclear neutrophils via its gingipains.
abstract: The Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, with the capacity to amplify pro-inflammatory cytokine production and regulate apoptosis. Polymorphonuclear neutrophils (PMNs) are the first line of defence against infection, and a major source of TREM-1. Porphyromonas gingivalis is a Gram-negative anaerobe highly implicated in the inflammatory processes governing periodontal disease, which is characterized by the destruction of the tooth-supporting tissues. It expresses a number of virulence factors, including the cysteine proteinases (or gingipains). The aim of this in vitro study was to investigate the effect of P. gingivalis on TREM-1 expression and production by primary human PMNs, and to evaluate the role of its gingipains in this process. After 4 h of challenge, P. gingivalis enhanced TREM-1 expression as identified by quantitative real-time PCR. This was followed by an increase in soluble (s)TREM-1 secretion over a period of 18 h, as determined by ELISA. At this time-point, the P. gingivalis-challenged PMNs exhibited diminished TREM-1 cell-membrane staining, as identified by flow cytometry and confocal laser scanning microscopy. Furthermore engagement of TREM-1, by means of anti-TREM-1 antibodies, enhanced the capacity of P. gingivalis to stimulate interleukin (IL)-8 production. Conversely, antagonism of TREM-1 using a synthetic peptide resulted in reduction of IL-8 secretion. Using isogenic P. gingivalis mutant strains, we identified the Arg-gingipain to be responsible for shedding of sTREM-1 from the PMN surface, whereas the Lys-gingipain had the capacity to degrade TREM-1. In conclusion, the differential regulation of TREM-1 by the P. gingivalis gingipains may present a novel mechanism by which P. gingivalis manipulates the host innate immune response helping to establish chronic periodontal inflammation.
authors.affiliation: Oral Translational Research, Institute of Oral Biology, Center of Dental Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Nagihan
authors.initials: N
authors.lastname: Bostanci
authors.forename: Thomas
authors.initials: T
authors.lastname: Thurnheer
authors.forename: Joseph
authors.initials: J
authors.lastname: Aduse-Opoku
authors.forename: Michael A
authors.initials: MA
authors.lastname: Curtis
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Georgios N
authors.initials: GN
authors.lastname: Belibasakis
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D003546:Cysteine Endopeptidases