DUSP1 and Sexual Dimorphism in Periodontitis

Periodontal disease progression is a consequence of the host immune inflammatory response to oral pathogens. Sexual dimorphism is evident in the innate immune system where lipopolysaccharide (LPS) derived from periodontal pathogens stimulates the production of cytokines and chemokines in a more robust manner in males compared to females contributing towards increase susceptibility of periodontal disease in males. The role of p38/MKP-1 signaling in chronic inflammation and periodontal disease progression supports the concept that MKP-1 signaling is vital to attenuate MAPK-induced innate immune cytokine expression at the post-transcriptional level through mRNA interaction with RNA binding proteins. In vivo models in periodontal and periapical bone loss indicate that in the absence of MKP-1, there is enhanced neutrophil infiltrate and inflammation in a sex-dependent manner. Based upon these data, we posit that MKP-1 plays a crucial role in regulating cytokine/chemokine production in activated neutrophil trafficking, chemokine signaling, and chemokine/cytokine gene regulation during periodontal disease progression contributing to the sexual dimorphism of the innate immune response observed in periodontitis. The specific aims of this application are to 1) Test the hypothesis that MKP-1 signaling contributes to neutrophil chemoattraction and function under inflammatory conditions through specific chemokine and cytokine deregulation contributing towards sex differences in the immune response; 2) Test the hypothesis that MKP-1 signaling regulates chemokine gene expression through post-transcriptional mechanisms in a sex-dependent manner; and 3) Test the hypothesis that DUSP1 gene is hypermethylated & silenced in periodontal disease tissues.. Foundation and translational significance of chemokine regulation through MKP-1 and mRNA stability will provide insight into the potential of these proteins to be targeted for future studies that will modify innate immune chemokine expression for therapeutic benefit.