Porphyromonas gingivalis-Induced NLRP3 Inflammasome Activation and Its Downstream Interleukin-1β Release Depend on Caspase-4

Background: Oral commensals contribute to microbe-host symbiosis in periodontal homeostasis, andPorphyromonas gingivalis(P. gingivalis) as the keystone pathogen critically accounts for the shift of symbiosis to dysbiosis and periodontal destruction. Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1 beta) is significantly involved in periodontal diseases, and notablyP. gingivalisenables to modulate the induction and expression of NLRP3. Whereas, the exact mechanism by which NLRP3 inflammasome is regulated in response to commensal and pathogenic bacteria remains unclear. Methods: To examine the expression of IL-1 beta and NLRPs inflammasome in tissues with severe chronic periodontitis, and further investigate how Caspase-4-dependent non-canonical NLRP3 inflammasome pathways functioned during the interactions ofStreptococcus mitis(S. mitis) andP. gingivaliswith human THP-1 cells. Results: IL-1 beta and NLRP3, NLRP6, NLRP12, and absent in melanoma 2 (AIM2) inflammasomes are highly expressed in gingival tissues with severe chronic periodontitis. In human THP-1 cells,P. gingivalisactivates the synthesis and secretion of IL-1 beta to higher levels thanS. mitis. Importantly, NLRP3-, Caspase-1-, and Caspase-4-siRNA knockdown THP-1 cells treated withP. gingivalisexhibited a lower expression level of IL-1 beta as compared to the control cells. In addition, silencing of either CASP4 or CASP1 can lead to a concurrent or reciprocal decrease in the expression of the other. Of note, the IL-1 beta induction is not affected in theS. mitis-treated THP-1 cells with the silence of NLRP3, Caspase-1, and Caspase-4 genes. Conclusion: NLRP3/Caspase-4 and NLRP3/Caspase-1 dependent IL-1 beta production may crucially contribute to the dysregulated immuno-inflammatory response in periodontal pathogenesis.