Saturday, April 20, 2024
4/20/2024
Project Summary/Abstract: Periodontitis is a chronic inflammatory disease induced by bacterial infection within the periodontium and affects almost 50% of adults in the United States. Unresolved inflammation in this area results in the breakdown of the periodontal ligament and alveolar bone which can lead to subsequent tooth loss. While the presence of bacteria initiates periodontitis, it is ultimately not the sole factor that drives disease progression. The inflammatory response is critical for the eradication of bacterial invaders, however the dysregulation of these mechanisms and overproduction of pro-inflammatory cytokines such as TNF-a, IL-6, IL-12 p40, and Macrophage Inflammatory Protein 2 (MIP-2) have been implicated in the progression of tissue damage in the periodontium and in other chronic inflammatory diseases. Histone deacetylase 6 (HDAC6) is a member of the class II HDACs located in the cytoplasm that can deacetylate specific non-histone proteins and facilitate their translocation to the nucleus. This deacetylation has been reported to alter production of inflammatory mediators in response to the stimulation of microbe-associated molecular patterns (MAMPs). Our preliminary results have shown that stimulation of innate immune cells with Porphyromonas gingivalis, a major pathogenic bacterium associated with chronic periodontitis, resulted in phosphorylation of class II HDACs and subsequent deacetylation of FoxO1, which will enhance its binding to the FoxO-binding element and thus promote associated pro-inflammatory mediator production. Likewise, selective inhibition of HDAC6 resulted in a decrease in pro-inflammatory cytokine production through increasing cytosolic translocation of FoxO1 and subsequently decreased its binding to the promoter of C/EBP-ß after P. gingivalis infection. Therefore, using P. gingivalis as a model organism, we hypothesize that oral bacterial pathogens activate HDAC6 and enhance the inflammatory response through facilitating the deacetylation and nuclear translocation of FoxO1, subsequently enhancing the expression of downstream pro-inflammatory mediators. We will test this hypothesis using two aims. Experiments proposed for Aim 1 will investigate the role of HDAC6 in the inflammatory response by observing the production of inflammatory cytokines and the migration of neutrophils and will also delineate the downstream signaling of HDAC6 in different immune cells in response to P. gingivalis challenge. In Aim 2, we will examine the in vivo relevancy of HDAC6 signaling in gingival tissue inflammatory responses to oral bacterial infection and alveolar bone loss. These aims will establish the regulatory function of HDAC6-mediated differential inflammatory mediator secretion in the control of immune responses. The long-term goal of this proposed work will be to identify novel interventional therapeutic targets and regulatory mechanisms of periodontal inflammation that may be broadly applicable to other inflammatory diseases.
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