A PNAS study reports that males and females show different inflammasome activity during periodontitis, with implications for interpreting inflammatory markers and considering sex-specific responses to targeted therapies.
Periodontitis is an inflammatory condition that leads to bone loss around teeth. It affects both sexes but is consistently more common and more severe in males. The biological basis for this difference has been unclear. The current study examined whether production of pro-inflammatory cytokine IL-1β differs by sex.
Across three human datasets, including more than 6,200 gingival crevicular fluid samples, males had higher IL-1β levels than females in both healthy tissue and in periodontitis. Male-derived neutrophils also secreted more IL-1β after stimulation, suggesting a sex-based difference in upstream inflammatory signaling.
To study this further, researchers used ligature-induced periodontitis models in mice. Male mice showed higher IL-1β production, more sustained inflammatory cell infiltration, and greater alveolar bone loss compared with females. These findings were consistent during both early and later stages of the disease.
Genetic deletion models clarified the role of inflammasome components. Male mice lacking IL-1β, ASC, or caspase-1/11 were protected from bone loss, while females with the same deletions did not show meaningful changes. This indicates that inflammasome-mediated IL-1β signaling is a key driver of bone resorption in males but not in females.
The study also tested the caspase-1/4 inhibitor VX-765. In males, the inhibitor reduced IL-1β levels, inflammatory cell infiltration, and osteoclast-related signaling, and it prevented bone loss. In females, these effects were not observed. Gonadectomy experiments showed that males required intact male reproductive organs to respond to the inhibitor, while ovariectomy did not alter the female response.
These findings suggest that IL-1β and other inflammasome-related markers may vary by sex and could influence how inflammatory profiles are interpreted in periodontitis research or clinical evaluation.
The authors conclude that males appear to rely more heavily on inflammasome-driven IL-1β activity during periodontal inflammation, whereas females may depend on different inflammatory pathways. They suggest that future diagnostic studies and treatment strategies may benefit from considering sex-specific inflammatory mechanisms.
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