Porphyromonas gingivalis Promotes Unrestrained Type I Interferon Production by Dysregulating TAM Signaling via MYD88 Degradation

Publication date: 10 January 2017
Source:Cell Reports, Volume 18, Issue 2
Author(s): Gabriel Mizraji, Maria Nassar, Hadas Segev, Hafiz Sharawi, Luba Eli-Berchoer, Tal Capucha, Tsipora Nir, Yaara Tabib, Avraham Maimon, Shira Dishon, Lior Shapira, Gabriel Nussbaum, Asaf Wilensky, Avi-Hai Hovav
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.

Graphical abstract

Teaser

Mizraji et al. found that elevated expression of type I interferons mediates murine periodontitis induced by the oral pathogen P. gingivalis. P. gingivalis causes degradation of MYD88 that is essential to the expression of AXL and GAS6, known negative regulators of type I interferons.


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