Abstract 1602 MyD88-Dependent Modulation of Macrophage Polarization by Simvastatin During Simulated Periodontal Inflammation

Periodontal disease (PD) is a chronic inflammatory disorder characterized by the destruction of connective tissue, tooth loss, and systemic infections. Clinically, treatment of PD includes control of the etiologic factors via several modalities: initial therapy, including scaling and root planing (SRP), corrective phase of surgical treatment, both with and without adjunct antimicrobial/pharmacological agents, followed by a maintenance/supportive periodontal therapy phase. Monotherapy of systemic antibiotics is insufficient compared to their use as an adjunct to SRP. The critical issue of systemic antimicrobial usage includes adverse patient outcomes and increased bacterial resistance. Therefore, alternative adjuncts to periodontal therapy have been sought. Statins are widely prescribed for the treatment of hypercholesterolemia and cardiovascular disease. Statins have demonstrated anti-inflammatory properties and immunomodulatory effects, and a few retrospective studies showed that statin patients exhibit fewer signs of periodontal inflammation than subjects without the medication. Despite the available clinical studies on the local administration of statins for PD, no studies have reported the macrophage polarization response. We have developed a gingival fibroblast–macrophage co-culture model to track macrophage response when exposed to a battery of microenvironmental cues mimicking macrophage polarization/depolarization observed in vivo. Using our model, we demonstrate that simvastatin suppresses macrophage inflammatory response and upregulates tissue homeostasis and alternative macrophage activation. Intending to study the host response to periodontal disease and develop adjunctive drug therapies, we clarify statins' role in periodontal disease's inflammatory effects. Furthermore, we determined the relative contributions of MyD88-dependent signaling pathways and the role of simvastatin in driving TLR-mediated macrophage polarization. Using a combination of statin and MyD88 inhibitor, we show that macrophage polarization is amplified in a MyD88-dependent manner, and simvastatin treatment further augmented the M2 state. When macrophages were treated with either simvastatin or MyD88 inhibitor, T6167923, during the PMA withdrawal and resting phase, the M2 phenotype was augmented with CD68hiCD163hiCD206int signature with the statin–MyD88 inhibitor-treated cells. We demonstrate a crucial mechanism of immune response modulation in PD by providing evidence in vitro that statins have anti-inflammatory effects. Our research methodology was designed to specifically understand how macrophage skewing contributes to PD in the downstream development of an immune response and design new therapeutics. Developmental research project award, SC IDeA Networks of Biomedical Research Excellence, University of South Carolina/NIH/NIGMS.