Macrophage-driven inflammatory cytokine networks in periodontitis and type II diabetes

Abstract

Periodontitis, a severe inflammatory condition triggered by bacterial accumulation in dental plaque, presents significant risks to oral health, potentially leading to alveolar bone loss and tooth loss. Moreover, severe periodontitis may have systemic effects, contributing to conditions such as type II diabetes (T2D), cardiovascular diseases, and an increased risk of respiratory infections. The pathophysiology of periodontal disease shares many features with these systemic inflammatory conditions including similar immunoinflammatory responses and complex cytokine networks that perpetuate inflammation. This overlap highlights the interconnected nature of oral and systemic health, underscoring the need for integrated management strategies.

Macrophages play a crucial role in periodontitis as primary effector cells of innate immunity. These cells maintain tissue homeostasis by releasing various pro- and anti-inflammatory factors, coordinating programmed cell death for tissue cleanup, and facilitating adaptive immune responses through antigen presentation. This dual role of macrophages in both inflammation and resolution indicates their importance in inflammatory diseases such as periodontitis and T2D.

One of the primary cytokines secreted by macrophages during inflammation is IFNβ, known for modulating immune responses possibly through inducing IL-10 or inhibiting the inflammasome and IL-1β production. However, IFNβ can also exacerbate inflammation by attracting Ly-6C+ monocytes to sites of chronic inflammation. This contradictory behavior of IFNβ underscores the need for further exploration to understand its specific roles and mechanisms in various inflammatory diseases, including periodontitis and T2D.

To address this, our initial phase of research involved a comprehensive literature review focused on the role of IFNβ in a spectrum of inflammatory diseases, with a particular emphasis on its interactions with macrophages. The complex dual role of IFNβ, acting as both a pro-inflammatory and anti-inflammatory agent, raises intriguing questions about its effects on periodontitis.

In order to gain a better understanding of the specific impact of IFNβ on macrophages under periodontitis, we utilized proteomics and single-cell analysis. Our findings suggest that IFNβ plays a crucial anti-inflammatory role in the pathogenesis of periodontitis, potentially suppressing excessive immune responses and facilitating inflammation resolution. This activity could create a more favorable environment for tissue regeneration, contributing to the healing and restoration of periodontal tissues.

Additionally, considering the link between periodontitis and T2D, we explored the cytokine networks between these conditions to understand their mutual influence. While IFNβ's presence did not significantly affect the coexistence of periodontitis and T2D, chemokine ligand 8 (CXCL8) emerged as a key mediator. Increased CXCL8 levels in macrophages responding to both conditions suggest its potential as a biomarker for the coexistence of these diseases. In summary, our comprehensive research into the role of IFNβ and CXCL8 in the context of periodontitis and its systemic connections to T2D underscores the complex interplay between cytokines and macrophages in inflammatory diseases. IFNβ predominantly plays an anti-inflammatory role, aiding tissue repair and inflammation resolution in periodontitis, and CXCL8 is a critical mediator and biomarker in the co-occurrence of periodontitis and T2D. These findings pave the way for targeted therapeutic strategies that could more effectively manage periodontitis and its associated systemic implications.