AUTHOR=Ding Pei-Hui , Yang Meng-Xin , Wang Na-Na , Jin Li-Jian , Dong Yan , Cai Xia , Chen Li-Li 

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

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.01881

DOI=10.3389/fmicb.2020.01881

ISSN=1664-302X

ABSTRACT=<p><bold>Background</bold>: Oral commensals contribute to microbe-host symbiosis in periodontal homeostasis, and <italic>Porphyromonas gingivalis</italic> (<italic>P. gingivalis</italic>) 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-1β (IL-1β) is significantly involved in periodontal diseases, and notably <italic>P. gingivalis</italic> enables 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.</p><p><bold>Methods</bold>: To examine the expression of IL-1β 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 of <italic>Streptococcus mitis</italic> (<italic>S. mitis</italic>) and <italic>P. gingivalis</italic> with human THP-1 cells.</p><p><bold>Results</bold>: IL-1β 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, <italic>P. gingivalis</italic> activates the synthesis and secretion of IL-1β to higher levels than <italic>S. mitis</italic>. Importantly, NLRP3-, Caspase-1-, and Caspase-4-siRNA knockdown THP-1 cells treated with <italic>P. gingivalis</italic> exhibited a lower expression level of IL-1β 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-1β induction is not affected in the <italic>S. mitis</italic>-treated THP-1 cells with the silence of NLRP3, Caspase-1, and Caspase-4 genes.</p><p><bold>Conclusion</bold>: NLRP3/Caspase-4 and NLRP3/Caspase-1 dependent IL-1β production may crucially contribute to the dysregulated immuno-inflammatory response in periodontal pathogenesis.</p>