Inflammasome dependent and independent dysregulation associated with periodontal disease and oral cancer risk in people with HIV

Introduction : People with HIV (PWH) exhibit immune dysregulation, which can increase their susceptibility to periodontal disease (PD), elevating the risk of chronic oral inflammation, tissue damage, and oncogenesis. Persistent periodontitis may drive the development of oral squamous cell carcinoma (OSCC) through increased prevalence of pathogenic bacteria and elevated levels of inflammatory cytokines. In fact, our preliminary data show dysbiosis of the oral microbiome associated with PD. Furthermore, PD can be associated with inflammasome dysfunction, which can impact downstream production of cytokines. In PWH, these inflammatory processes may be exacerbated, fostering a pro-oncogenic microenvironment. This study aims to quantify levels of inflammasomes and inflammatory markers in PWH and evaluate their association with PD and OSCC risk. Methods: Saliva and oral rinse samples, along with sociodemographic and clinical data, were collected from 202 virologically suppressed PWH. A comprehensive periodontal assessment was performed, and participants were categorized into four groups based on PD severity: none, mild, moderate, and severe. Protein levels of inflammasomes (NLRP3 and NLRC4) were quantified in saliva using ELISA, while cytokine concentrations (IL-1beta, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-alpha) were quantified using ELLA. Statistical analyses were performed using R statistical software. Median values were compared using Mann-whitney or Krukal-wallis tests with post-hoc adjustment. Results: Participants with PD exhibited significantly higher levels of IL-1beta (400 pg/mL vs 235 pg/mL, p<0.01), IL-6 (25.4 pg/mL vs 14.2 pg/mL, p<0.01), and IL-8 (798 pg/mL vs 549 pg/mL, p=0.04) while there was a trend for higher levels of IL-17 (2.01 pg/mL vs 1.50 pg/mL, p=0.05). In addition, IL-1beta was significantly higher in subjects with moderate (408 pg/mL, p=0.01) and severe PD (378 pg/mL, p=0.01) when compared to no PD (235 pg/mL). On the other hand, while there was no significant difference in the levels of NLRP3 and NLRC4 by PD status, people with severe PD (3.37 ng/mL) had significantly lower levels of NLRP3 when compared to moderate (5.83 ng/mL, p<0.01) or no PD (5.71 ng/mL, p=0.02). Conclusion: There were increased levels of inflammatory cytokines, particularly IL-1B, and alterations to inflammasome levels according to PD severity, supporting the role of pyroptosis in the pathogenesis of PD. Chronic elevation of additional pyroptosis independent inflammatory cytokines and dysbiosis of the oral microbiome may contribute to a persistent inflammatory microenvironment associated with increased OSCC risk in PWH. These results highlight the importance of monitoring oral cytokine profiles as both biomarkers of disease progression and potential indicators of cancer risk in PWH.