Year: 2025
Type: article
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.
Authors: Tomaz Alves, Karen V. Swanson, Mustafa S. Girnary, Marcelo Freire, Kevin Moss, Kimon Divaris, James Beck, Pollyana Coelho Pessoa Santos, W. June Brickey, John A. Wrobel, Heidi Yeigi Min, Manaal Syed, Thiago Morelli, William T. Seaman, John S. Preisser, Di Hu, Hannah Preisser, Natalia Makhanova, Cristiano Susin, Nishma P. Vias, Maya Styner, Shaoping Zhang, Flavia Queiroz Pirih, Jia Chang, Harvinder Singh Gill, Adam D. Lietzan, Jennifer Webster-Cyriaque, Jenny P. Y. Ting, Julie T. Marchesan
Institutions: University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, J. Craig Venter Institute, University of California San Diego, Indiana University School of Medicine, National Institutes of Health, National Institute of Dental and Craniofacial Research, University of Iowa, University of California, Los Angeles, North Carolina State University
Language: English
Subfield: Periodontics
Field: Dentistry
Domain: Health Sciences
Open Access status: hybrid
Funders: U.S. Department of Health and Human Services, American Association for Dental, Oral, and Craniofacial Research, Division of Cancer Prevention, National Cancer Institute, 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 Institute of Dental and Craniofacial Research, National Center for Advancing Translational Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Awards: G1114307781, G1522370804, Regulation of ChemR23 in Resolution of Inflammation, G1736314383, G1788514665, G1823732541, G2262505034, IFI16 is a Periodontitis Modulating Protein, G2828052670, Plexin-A1: Regulation by CIITA and Immunologic Function, G3744596180, G38957974, G3973572274, G407118926, G4464843077, G446737828, G4597579782, G4739409156, G4747441672, G4790942633, G5352314984, Centers for Medical Countermeasures Against Radiation, Role and Mitigation of Inflammasomes and Inflammation During COVID-19, G5770678025, G5928944960, Molecular control of bone development and inflammation by FBXO11, G6060132884, Exploring the Ecological Role of Rothia mucilaginosa and It's Iron Binding Siderophore Enterobactin, North Carolina Translational and Clinical Science Institute (NC TraCS), G6739173425, G6837735701, G6929966040, G6962385986, G6975186798, G7155745631, Plexin-A1: Regulation by CIITA and immunologic function, G7366156696, G7535686976, G8455006929, G8738262636, G893857917, G9000033364, G9000072125, G9000168410, G9000194837, Inflammasome regulation underlying sexual dimorphism in periodontitis, Molecular and Functional Analysis of Innate Immune Receptors, Role and Mitigation of Inflammasomes and Inflammation During COVID-19, Intracellular Innate Immune Receptors in Cancer Suppression and Immunotherapy, Host Factors for Rhinovirus, Cancer Center Support Grant, North Carolina Translational and Clinical Sciences Institute (NC TraCS), G958207224
OpenAlex ID: W4415595818