Inflammasome targeting for periodontitis prevention is sex dependent

Inflammasome initiates inflammation via the maturation of interleukin-1 beta (IL-1β). Periodontitis is a prevalent, male-biased disease characterized by inflammation-driven bone loss, yet the mechanism(s) of this sex bias is unknown. This study explored whether enhanced inflammasome represents a causal mechanism for this bias. Analyses of three separate human studies (>6,200 samples) show that males have significantly higher IL-1β in the gingival crevicular fluid than females during health and periodontitis. This pattern is experimentally reproduced with different versions of the ligature-induced periodontitis mouse model where males show greater IL-1β secretion than females. The inflammasome drives bone resorption in males but not females as revealed by analyses of inflammasome gene-deletion mice. Pharmacologic treatment with a caspase-1/4 inhibitor reduces inflammatory cell infiltration, dampens osteoclastogenesis signaling (via the receptor activator of nuclear factor-kappa B pathway), and prevents bone resorption in males but not females during experimental periodontitis. While ovariectomized females show no change in their nonresponsiveness to caspase-1/4 inhibition, orchiectomized males no longer respond to the inhibition, suggesting the importance of an intact male reproductive system in the mediation of this inhibition. Thus, our study identifies inflammasome activation as causal for male-biased experimental periodontitis and supports sex-stratified studies to foster future advancement of inflammasome therapeutics in periodontics.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-10-27
DOI
https://doi.org/10.1073/pnas.2507092122
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

Inflammasome targeting for periodontitis prevention is sex dependent

Chang Jia, Pollyana C. P. Santos, Jenny P.‐Y. Ting, W. June Brickey et al.
Proceedings of the National Academy of Sciences
Inflammasome and immune disorders
article

Inflammasome targeting for periodontitis prevention is sex dependent

Chang Jia, Pollyana C. P. Santos, Jenny P.‐Y. Ting, W. June Brickey, Thiago Morelli, Harvinder Singh Gill, Kevin Moss, Julie T. Marchesan, John A. Wrobel, William T. Seaman, Mustafa Girnary, Karen V. Swanson, Di Hu, Marcelo Freire, Nishma P. Vias, James D. Beck, Manaal Syed, Kimon Divaris, Adam D. Lietzan, Flávia Q. Pirih, Tomaz Alves, Cristiano Susin, John S. Preisser, Shaoping Zhang, Maya Styner, Jennifer Webster‐Cyriaque, H.K. Min, Hannah Preisser, Natalia Makhanova
article en

Abstract

Inflammasome initiates inflammation via the maturation of interleukin-1 beta (IL-1β). Periodontitis is a prevalent, male-biased disease characterized by inflammation-driven bone loss, yet the mechanism(s) of this sex bias is unknown. This study explored whether enhanced inflammasome represents a causal mechanism for this bias. Analyses of three separate human studies (>6,200 samples) show that males have significantly higher IL-1β in the gingival crevicular fluid than females during health and periodontitis. This pattern is experimentally reproduced with different versions of the ligature-induced periodontitis mouse model where males show greater IL-1β secretion than females. The inflammasome drives bone resorption in males but not females as revealed by analyses of inflammasome gene-deletion mice. Pharmacologic treatment with a caspase-1/4 inhibitor reduces inflammatory cell infiltration, dampens osteoclastogenesis signaling (via the receptor activator of nuclear factor-kappa B pathway), and prevents bone resorption in males but not females during experimental periodontitis. While ovariectomized females show no change in their nonresponsiveness to caspase-1/4 inhibition, orchiectomized males no longer respond to the inhibition, suggesting the importance of an intact male reproductive system in the mediation of this inhibition. Thus, our study identifies inflammasome activation as causal for male-biased experimental periodontitis and supports sex-stratified studies to foster future advancement of inflammasome therapeutics in periodontics.

Proceedings of the National Academy of SciencesVol. 122(44)
University of North Carolina at Chapel Hill (US), University of Iowa (US), Indiana University Health (US), National Institutes of Health (US), J. Craig Venter Institute (US), North Carolina State University (US), University of California, Los Angeles (US), Duke University (US), Massachusetts College of Liberal Arts (US), American Association of Endodontists (US), University of California System (US), University of California San Diego (US), National Institute of Dental and Craniofacial Research (US), Regenerative Medicine Institute (MX), North Carolina Division of Public Health (US), UNC Lineberger Comprehensive Cancer Center, Indiana University – Purdue University Indianapolis (US), Indiana University (US)
U.S. Department of Health and Human Services, American Association for Dental, Oral, and Craniofacial Research, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Openalex Percentile: Top 72%
Inflammasome and immune disorders
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