Despite S. mitis-induced IL-1β secretion was hardly related to the signaling pathway mediated by NLRP3/Caspase-1/Caspase-4, P. gingivalis could modulate NLRP3 inflammasome activation through both canonical Caspase-1-dependent and non-canonical Caspase-4 pathways, leading to a much more intense inflammatory response including Caspase-1 activation and IL-1β release during infection, which may crucially contribute to the dysregulated immuno-inflammatory response in periodontal pathogenesis. Here, CASP4 is linked to infection.