Inflammasome regulation underlying sexual dimorphism in periodontitis

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ABSTRACT Periodontitis is a male-dominant, heterogeneous, inflammatory disease of the bone and tissues supporting the tooth. It is one of the most prevalent non-communicable chronic diseases, with ~50% prevalence in the American population. Currently, there are no adjuvant therapies available to treat the 20-25% of “hyper-inflammatory” patients that progress to tooth loss despite appropriate standard of care. In support of this current proposal, inflammasome modulation has been proposed to treat several inflammatory diseases. Inflammasome is required for processing of pro-interleukin (IL)-1, pro-IL-18, and Gasdermin-D into their mature, functional forms. Despite the common knowledge that IL-1 is sexually dimorphic and a marker for periodontal inflammation, its role as a direct driver of disease development in both females and males is not clear. We find that inflammasome activation has both a protective and destructive effect on periodontal tissue that is differentially regulated between the sexes. Our data suggest the existence of sex-based distinct pathways of periodontal bone loss. This study will expand our current knowledge on the role of inflammasomes in periodontal inflammation and tissue destruction in females and males. We propose to build upon our findings to develop the below aims: Aim 1: Define the impact of biological sex in inflammasome activation during periodontal disease development and progression. Aim 2: Define the relationship between inflammasomes and periodontal tissue repair. Aim 3: To use a new strategy to target inflammasomes for preventing murine periodontitis. 1