Elucidating The Immunoregulatory Role of Dendritic Cell Subsets in Periodontal Disease

Periodontal disease (PD) is a chronic inflammatory disease of periodontium that affects the supporting structures of the teeth. It is the sixth most common disease affecting ~750 million people worldwide and the prevalence and severity of PD is becoming a major health concern. This chronic disease is driven by an uncontrolled immune response to bacterial overgrowth. Multiple studies have shown the pro-inflammatory role of immune cells such as macrophages (Mφ), dendritic cells (DC), T cells, and B cells in the development of PD. Dendritic cells (DC) are key antigen-presenting cells (APC) and the predominant immune cells capable of activating T cell response. Three major DC subsets viz., myeloid DC (mDC), lymphoid DC (lDC), and plasmacytoid DC (pDC) are known in humans and mice. While their role in periodontal disease is well-described, how these subsets respond during the disease resolution and their functional interaction with periodontal bacteria remains unexplored. In this proposal, we will investigate the dynamic of DC subsets in ex vivo human gingival biopsies collected pre- and post-non-surgical periodontal therapy (NSPT). PD is mediated by dysbiosis of key bacterial species, including A. actinomycetemcomitans and P. gingivalis; therefore, we aim to assess how periopathic bacteria or their virulence factors impair the functions of DC subsets. We will evaluate antigen processing/presentation, phagocytosis, and IFN type I immune response functions of different DC subsets in the presence of periopathic bacteria. Our preliminary results show a differential expression of mDC and lDC in inflamed gingiva. In the presence of A. actinomycetemcomitans, mDCs promote proliferation of CD4+ T cells suggesting a role of periopathic bacteria in DC function. Understanding how these cells interact with periopathic bacteria and shape their immune activity could lead to new treatments for periodontal disease. Next, we will perform infiltration kinetics of various DC subsets and adaptive immune cells in the ligature-induced periodontitis (LIP) and resolution mice models. The immunoregulatory role of major DC subsets will be characterized using an adoptive transfer approach in LIP and resolution models. Finally, DC subsets exhibiting a pathogenic or immunoregulatory role identified in the adoptive transfer experiments, will be targeted by known DC subset inhibitors to mitigate PD or promote disease resolution, respectively. The knowledge gained will advance our understanding of DC subsets during periodontal disease and its resolution and provide valuable insights for developing targeted therapies to either prevent disease progression or promote healing. Project Number: 1R03DE035551-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Araceli Valverde | Institution: UNIVERSITY OF ILLINOIS AT CHICAGO, Chicago, IL | Award Amount: $320,660 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 MSOS-M (52)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11287666