Introduction

The human immune system is remarkably complex, serving as a powerful defense network against a multitude of pathogens. It is broadly classified into two main types: innate immunity and adaptive immunity. Innate immunity acts as the first line of defense, deploying various immune cells like monocytes, macrophages, dendritic cells, granulocytes, natural killer (NK) cells, and NKT cells to recognize and combat pathogens. For instance, the lipopolysaccharides (LPS) derived from Gram-negative bacteria can be detected by receptors like Toll-like receptor 4 (TLR-4) on immune cells, triggering an innate immune response.

Adaptive immunity, on the other hand, is more sophisticated, involving lymphocytes such as B cells and T cells. B cells generate antibodies against extracellular threats, while T cells specialize in targeting intracellular pathogens. The interplay between these two types of immunity is crucial: innate immunity not only initiates the adaptive response but also fine-tunes it through various signaling pathways.

Among the myriad of signals involved in immune response, interleukin-17A (IL-17A) has emerged as a central player, orchestrating both protective and destructive immune mechanisms. Understanding its role, particularly in the context of periodontitis-an inflammatory condition of the supporting structures of the teeth-can unveil new frontiers in treating not just oral health issues but also broader systemic inflammatory diseases.

Periodontitis: A Chronic Inflammatory Disease

Periodontitis is a chronic inflammatory disease characterized by the destruction of periodontal tissues, primarily resulting from microbial infections and the host's immune responses. It represents a significant health concern, being the leading cause of tooth loss in adults worldwide, and is also considered an independent risk factor for systemic diseases such as rheumatoid arthritis, diabetes, and cardiovascular diseases.

Pathogen-associated microorganisms in dental plaque can provoke an inflammatory response, leading to tissue damage, including periodontal ligament destruction and alveolar bone resorption. Host immune responses are primarily responsible for the damage; while they aim to eliminate the pathogens, they can inadvertently harm local tissues. This duality of host responses highlights the protective yet destructive aspects of immunity.

Fig. 1 An anatomical illustration of periodontitis (Feng Y., et al. 2022).

The Role of IL-17A in Periodontitis

The cytokine IL-17A, produced by various immune cell types, including Th17 cells and other innate immune cells, plays a critical role in the pathogenesis of periodontitis. Research has demonstrated that patients with chronic periodontitis exhibit elevated levels of IL-17A in gingival tissues compared to healthy individuals. This elevation correlates with tissue destruction and the inflammatory response observed in periodontitis.

IL-17A promotes the recruitment and activation of neutrophils to the sites of infection, enhancing the phagocytic response against periodontal pathogens. However, while neutrophils are essential for clearing infections, their excessive activation can lead to collateral tissue damage. Additionally, IL-17A induces osteoblasts to produce RANKL (Receptor Activator of Nuclear factor Kappa-Β Ligand), promoting osteoclast differentiation and subsequent bone resorption, a hallmark of periodontitis.

Furthermore, IL-17A has been shown to enhance the secretion of matrix metalloproteinases (MMPs) from gingival fibroblasts, contributing to the degradation of the extracellular matrix and periodontal tissue destruction. This destructive cycle underscores the complex role of IL-17A in mediating both protective immunity and inflammatory tissue damage.

IL-17A and Systemic Chronic Inflammatory Diseases

The interplay between periodontitis and systemic chronic inflammatory diseases has garnered increasing attention. Conditions such as rheumatoid arthritis (RA), psoriasis, and diabetes exhibit significant associations with periodontitis, where IL-17A serves as a common inflammatory mediator.

Relationship between Periodontitis and Rheumatoid Arthritis

Rheumatoid arthritis is characterized by synovitis and joint destruction driven by a dysregulated immune response. Evidence indicates a higher prevalence and severity of periodontitis among RA patients. The shared cytokine profile of both conditions, characterized by increased levels of IL-17A, TNF-α, and other pro-inflammatory mediators, suggests a potential link between chronic inflammation in periodontal tissues and systemic autoimmune responses.

Studies have shown that periodontitis may serve as a reservoir for autoantigens that can trigger or exacerbate RA. Moreover, treating periodontal disease has been associated with improved rheumatoid symptoms, further supporting the relationship between these two diseases.

Interactions between Periodontitis and Psoriasis

Psoriasis, another autoimmune inflammatory disease, shares overlapping immunological characteristics with periodontitis. Both conditions feature elevated IL-17A levels and exhibit an inflammatory response that impacts mucosal immunity. Recent clinical studies suggest that effective periodontal treatment can lead to reduced psoriasis severity, highlighting the potential interdependence between these conditions.

Periodontitis and Diabetes Mellitus

Diabetes mellitus, particularly type 2 diabetes (T2DM), has been shown to exhibit a bidirectional relationship with periodontitis. Elevated serum IL-17A levels have been identified in patients with T2DM and chronic periodontitis. Inflammatory responses in periodontitis may exacerbate insulin resistance, while poor glycemic control can further complicate periodontal health. Thus, managing periodontal disease may contribute to better control of diabetes and lower associated complications.

Therapeutic Insights: Targeting IL-17A

Given the pivotal role of IL-17A in mediating both local periodontitis and systemic inflammatory disease processes, targeting this cytokine represents a viable therapeutic strategy. Currently, IL-17A inhibitors, such as Secukinumab and Ixekizumab, have demonstrated efficacy in treating psoriasis, RA, and other inflammatory diseases. However, their application in periodontitis remains largely unexplored.

Preliminary studies in animal models have indicated that neutralizing IL-17A in periodontal tissues may mitigate inflammatory bone loss in periodontitis. However, more extensive human clinical trials are necessary to ascertain the safety and efficacy of IL-17A inhibitors for periodontitis treatment.

Conclusion

IL-17A is a key cytokine in the interconnected pathology of periodontitis and systemic chronic inflammatory diseases. Its dual role in mediating protective host responses and contributing to inflammatory tissue damage underscores the complexity of immune regulation. Further research elucidating the mechanisms underpinning IL-17A's role in these conditions is essential to developing targeted therapeutic strategies.

In summary, understanding the relationship between IL-17A, periodontitis, and systemic chronic inflammatory diseases is crucial for enhancing clinical diagnosis and treatment. This knowledge may pave the way for innovative approaches that address both oral and systemic health, ultimately leading to improved patient outcomes in those suffering from periodontitis and related systemic conditions.