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.

The Pros1/Tyro3 axis protects against periodontitis by modulating STAT/SOCS signalling

“…Mertk was similar to that of healthy control. 19 In this study, we also detected increased Pros1 and decreased…”

“…were down-regulated by LPS stimulation or repeated P gingivalis infection. 19,34 In this study, both Pros1 and Tyro3 were down- the expression of TNF-α, IL-6 and IL-1β by macrophages in response to LPS stimulation in a TAM receptor-dependent manner. 34 In this work, Pros1 inhibited p.g-LPs-induced production of TNF-α, IL-6, IL-1β, MMP9/2 and RANKL by hGECs in a Tyro3-dependent manner.…”

Oral infection with P. gingivalis exacerbates autoimmune encephalomyelitis

“…Interestingly, oral infection with P. gingivalis , a model for experimental periodontitis, also augmented the severity of EAE in a similar manner. In contrast to the acute inflammatory response in the subcutaneous chambers, oral infection is a chronic infection characterized by a continued inflammatory condition . This indicates that the effect of infection on EAE development is associated with either acute or chronic inflammatory responses.…”

“…Control group received the vehicle (PBS with 2% carboxymethycellulose (Sigma Aldrich, Rehovot, Israel)). Validation of bacterial presence in the oral microbiome and induction of bone loss following P. gingivalis oral infection are presented in a previous study …”

Biological links in periodontitis and rheumatoid arthritis: Discovery via text‐mining PubMed abstracts

“…Ubiquination has been recently implicated in periodontitis . P. gingivalis produces a ubiquitin‐ligase Smurf‐1 dependent degradation of MyD88, an upstream regulator NF‐κB in neutrophils, and results in elevated type‐1 interferon . Type‐1 interferon is increased in RA and correlated to ACPA production and drug response .…”