Inflammasome targeting for periodontitis prevention is sex dependent

作者：Tomaz Alves, Karen V. Swanson, Mustafa Girnary, Marcelo Freire, Kevin Moss, Kimon Divaris, James D. Beck, Pollyana C. P. Santos, W. June Brickey, John A. Wrobel, H.K. 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, Flávia Q. Pirih, Chang Jia, Harvinder Singh Gill, Adam D. Lietzan, Jennifer Webster‐Cyriaque, Jenny P.‐Y. Ting, Julie T. Marchesan · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2507092122 · 被引用次数：4 · 研究领域：Inflammasome and immune disorders、Oral microbiology and periodontitis research、Streptococcal Infections and Treatments

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 ...