A complex of NLRP3 with caspase-4 is essential for inflammasome activation by <i>Tannerella forsythia</i> infection

Periodontitis, a chronic inflammatory disease of periodontal tissue, is often associated with a group of pathogenic bacteria known as the "red complex", including Tannerella forsythia. Previous papers showed that T. forsythia induces many kinds of inflammatory cytokines including interleukin (IL)-1β regulated by inflammasome activation. However, the physiological function of periodontitis and the mechanism to induce inflammasome activation by T. forsythia infection are poorly understood. In this study, we demonstrate that the Nod-like receptor pyrin domain containing 3 (NLRP3) and caspase-4 are essential for inflammasome activation by T. forsythia infection, playing a crucial role in IL-1β maturation in THP-1 cells. We also showed that the knockout of ASC or Gasdermin D suppresses pyroptotic cell death. Moreover, co-immunoprecipitation assays confirmed the formation of a complex involving caspase-4, NLRP3, and ASC following T. forsythia infection. Additionally, reactive oxygen species production was identified as a key factor in caspase-4-mediated NLRP3 inflammasome activation by T. forsythia infection. These results enhance our understanding of inflammasome activation in response to T. forsythia infection and provide new insights into the pathogenic mechanisms of periodontitis.