Why does the inflammatory gum disease periodontitis tend to be worse in men versus women? As a possible answer to that question, researchers here demonstrate a sex difference in mammals in the inflammatory processes that drive the pathology of periodontitis. The condition progresses from chronic inflammation to bone loss and tooth loss, one example amongst many of the way in which unresolved inflammatory signaling changes the behavior of cells for the worse to cause disruption to tissue structure and function.
The 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 mechanisms of this sex bias is unknown. This study explored whether enhanced inflammasome activity represents a causal mechanism for this bias. Analyses of three separate human studies (more than 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 (RANKL) 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.
Link: https://doi.org/10.1073/pnas.2507092122
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