title: Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation.
abstract: Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4+T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL). Blocking IFN-I signaling restored proper immunological function and prevented ABL. Importantly, a loss of negative regulation on IFN-I expression by TAM signaling was also evident in periodontitis patients. These findings thus suggest a role for IFN-I in the pathogenesis of periodontitis.
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel; Department of Periodontology, Faculty of Dental Medicine, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mizraji
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Nassar
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Segev
authors.affiliation: Department of Periodontology, Faculty of Dental Medicine, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel.
authors.forename: Hafiz
authors.initials: H
authors.lastname: Sharawi
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Luba
authors.initials: L
authors.lastname: Eli-Berchoer
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Capucha
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tsipora
authors.initials: T
authors.lastname: Nir
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Yaara
authors.initials: Y
authors.lastname: Tabib
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Maimon
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Dishon
authors.affiliation: Department of Periodontology, Faculty of Dental Medicine, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Shapira
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nussbaum
authors.affiliation: Department of Periodontology, Faculty of Dental Medicine, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel. Electronic address: asafw@ekmd.huji.ac.il.
authors.forename: Asaf
authors.initials: A
authors.lastname: Wilensky
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel. Electronic address: avihaih@ekmd.huji.ac.il.
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
mesh_terms: D016301:Alveolar Bone Loss / Q000150:complications / Q000276:immunology / Q000473:pathology; D000818:Animals; D016866:Bacteroidaceae Infections / Q000150:complications / Q000276:immunology / Q000382:microbiology; D001862:Bone Resorption / Q000150:complications / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D005881:Gingiva / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009061:Mouth Mucosa / Q000382:microbiology / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010518:Periodontitis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000502:physiology*; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface
keywords: GAS6; Porphyromonas gingivalis, MYD88; interferon; mucosal immunity; oral mucosa; periodontitis