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Inflammasome targeting for periodontitis prevention is sex dependent
Journal article   Open access   Peer reviewed

Inflammasome targeting for periodontitis prevention is sex dependent

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, …
Proceedings of the National Academy of Sciences - PNAS, Vol.122(44), e2507092122
11/04/2025
DOI: 10.1073/pnas.2507092122
PMCID: PMC12595481
PMID: 41144672
url
https://doi.org/10.1073/pnas.2507092122View
Published (Version of record) Open Access

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.
 Animals Bone Resorption - prevention & control Caspase 1 - genetics Caspase 1 - metabolism Caspases, Initiator - metabolism Disease Models, Animal Female Gingival Crevicular Fluid - metabolism Humans Inflammasomes - genetics Inflammasomes - metabolism Interleukin-1beta - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Periodontitis - metabolism Periodontitis - pathology Periodontitis - prevention & control Sex Factors

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