Homeostasis between pro- and anti- inflammatory responses induced by bacteria is critical for the maintenance of health. In the oral cavity, pro-inflammatory mechanisms induced by pathogenic bacteria are well-established; however, the anti-inflammatory responses that act to restrain innate responses remain poorly characterized. Here, we demonstrate that infection with the periodontal pathogen Porphyromonas gingivalis enhances the activity of Janus kinase 3 (JAK3) in innate immune cells, and subsequently phospho-inactivates Nedd4-2, an ubiquitin E3 ligase. In turn, Wingless-INT (Wnt) 3 (Wnt3) ubiquitination is decreased, while total protein levels are enhanced, leading to a reduction in pro-inflammatory cytokine levels. In contrast, JAK3 or Wnt3a inhibition robustly enhances nuclear factor kappa-light-chain-enhancer of activated B cells activity and the production of pro-inflammatory cytokines in P. gingivalis-stimulated innate immune cells. Moreover, using gain- and loss-of-function approaches, we demonstrate that downstream molecules of Wnt3a signaling, including Dvl3 and β-catenin, are responsible for the negative regulatory role of Wnt3a. In addition, using an in vivo P. gingivalis-mediated periodontal disease model, we show that JAK3 inhibition enhances infiltration of inflammatory cells, reduces expression of Wnt3a and Dvl3 in P. gingivalis-infected gingival tissues, and increases disease severity. Together, our results reveal a new anti-inflammatory role for JAK3 in innate immune cells and show that the underlying signaling pathway involves Nedd4-2-mediated Wnt3a ubiquitination.
Keywords: P. gingivalis; JAK3; Wnt3; inflammation; ubiquitination.
© 2020 Federation of American Societies for Experimental Biology.