Polymicrobial-driven NLRP6 inflammasome regulates IL-1β production and alveolar bone loss in a murine model of periodontitis
- 1Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, United States of America
- 2Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- 3Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, United States of America
Abstract
Periodontal disease is a chronic inflammatory condition that develops in response to oral microbiome dysbiosis and host-microbiome immune response dysregulation. The innate immune system plays a major role in the development and persistence of disease, in part by producing inflammatory cytokines. One of the major cytokines implicated in disease is interleukin-1β (IL-1β), which requires inflammasome activation. Much of the oral microbiome, including Streptococci, which are otherwise considered commensal, is required for the full development of periodontal disease. We have previously reported that inflammatory-activated macrophages and neutrophils counterintuitively allow survival of internalized Streptococcus gordonii over non-activated phagocytes. This internal bacterial survival leads to inflammasome activation via the cytoplasmic activator NLRP6, but not NLRP3, and subsequent increases in IL-1β release. Here, we test and find that the keystone pathogen Porphyromonas gingivalis can activate macrophages in a manner that allows for increased S. gordonii survival and IL-1β production above levels when P. gingivalis interacts with macrophages alone. We also use the mouse ligature-induced periodontal disease model to test the importance of NLRP6 in disease development. We found mice lacking NLRP6 had significantly reduced bone loss, IL-1β, and neutrophil infiltration following disease induced by P. gingivalis when S. gordonii or other mouse commensals were present, but had no effect when S. gordonii was inoculated alone. This work thus reveals an additional important inflammasome activation mechanism by which oral keystone pathogens may stimulate periodontal disease progression. Author summary: Chronic inflammation is a driver of many diseases, including periodontal disease. Periodontal disease is a long-lasting inflammatory disease caused by an unhealthy imbalance in the oral microbiome and an abnormal immune response toward those bacteria. A major inflammatory molecule involved in this inflammation is IL-1β, which is produced after inflammasome activation. We previously found that immune cells such as macrophages and neutrophils can unexpectedly allow Streptococcus gordonii, a normally health-associated oral bacterium, to survive within the immune cells and to trigger the NLRP6 inflammasome, leading to increased IL-1β release. In this study, we found that Porphyromonas gingivalis, a key periodontal pathogen, stimulates macrophages to allow S. gordonii survival and increased IL-1β production. Using a mouse model of periodontal disease, we also found that without NLRP6 mice had less bone loss, less inflammation, and fewer neutrophils when P. gingivalis was present along with other oral bacteria. These results show that NLRP6 plays an important role in how oral bacteria work together to worsen periodontal disease.
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BibTeX
@article{metcalfe2026polymicrobialdriven,
title = {{Polymicrobial-driven NLRP6 inflammasome regulates IL-1β production and alveolar bone loss in a murine model of periodontitis}},
author = {Sarah Metcalfe and Rajendra P. Settem and Edwin J. Ovalle and Michelle Panasiewicz and Alejandro Escobar and Jason G. Kay},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014574},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014574},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Polymicrobial-driven NLRP6 inflammasome regulates IL-1β production and alveolar bone loss in a murine model of periodontitis
AU - Sarah Metcalfe
AU - Rajendra P. Settem
AU - Edwin J. Ovalle
AU - Michelle Panasiewicz
AU - Alejandro Escobar
AU - Jason G. Kay
PY - 2026
DA - 2026/09/15
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014574
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014574
AB - Periodontal disease is a chronic inflammatory condition that develops in response to oral microbiome dysbiosis and host-microbiome immune response dysregulation. The innate immune system plays a major role in the development and persistence of disease, in part by producing inflammatory cytokines. One of the major cytokines implicated in disease is interleukin-1β (IL-1β), which requires inflammasome activation. Much of the oral microbiome, including Streptococci, which are otherwise considered commensal, is required for the full development of periodontal disease. We have previously reported that inflammatory-activated macrophages and neutrophils counterintuitively allow survival of internalized Streptococcus gordonii over non-activated phagocytes. This internal bacterial survival leads to inflammasome activation via the cytoplasmic activator NLRP6, but not NLRP3, and subsequent increases in IL-1β release. Here, we test and find that the keystone pathogen Porphyromonas gingivalis can activate macrophages in a manner that allows for increased S. gordonii survival and IL-1β production above levels when P. gingivalis interacts with macrophages alone. We also use the mouse ligature-induced periodontal disease model to test the importance of NLRP6 in disease development. We found mice lacking NLRP6 had significantly reduced bone loss, IL-1β, and neutrophil infiltration following disease induced by P. gingivalis when S. gordonii or other mouse commensals were present, but had no effect when S. gordonii was inoculated alone. This work thus reveals an additional important inflammasome activation mechanism by which oral keystone pathogens may stimulate periodontal disease progression. Author summary: Chronic inflammation is a driver of many diseases, including periodontal disease. Periodontal disease is a long-lasting inflammatory disease caused by an unhealthy imbalance in the oral microbiome and an abnormal immune response toward those bacteria. A major inflammatory molecule involved in this inflammation is IL-1β, which is produced after inflammasome activation. We previously found that immune cells such as macrophages and neutrophils can unexpectedly allow Streptococcus gordonii, a normally health-associated oral bacterium, to survive within the immune cells and to trigger the NLRP6 inflammasome, leading to increased IL-1β release. In this study, we found that Porphyromonas gingivalis, a key periodontal pathogen, stimulates macrophages to allow S. gordonii survival and increased IL-1β production. Using a mouse model of periodontal disease, we also found that without NLRP6 mice had less bone loss, less inflammation, and fewer neutrophils when P. gingivalis was present along with other oral bacteria. These results show that NLRP6 plays an important role in how oral bacteria work together to worsen periodontal disease.
SN - 1553-7374
ER -