Mechanisms Linking S100A8/A9 to Th17 Cell Responses

The S100A8/A9 complex promotes Th17 cell responses via dendritic cells (DCs). It enhances the expression of major histocompatibility complex II (MHC II) and Th17-polarizing cytokines such as IL-6 and IL-23, leading to robust Th17 differentiation. This mechanism is mediated through the activation of the Acod1/STAT3 pathway (Wei et al., 2025).

Inhibition of S100A8/A9 has been shown to decrease the frequency of Th17 cells in the lacrimal glands and systemic compartments of SjDED mouse models, suggesting a therapeutic avenue for managing this condition. The therapeutic effect of paquinimod, a S100A8/A9 inhibitor, further supports this hypothesis by significantly ameliorating clinical symptoms and reducing inflammatory cell infiltration in the lacrimal glands (Liang et al., 2024).

Therapeutic Potential of Targeting S100A8/A9/Acod1/STAT3

Targeting the S100A8/A9/Acod1/STAT3 signaling axis presents a promising strategy in the treatment of SjDED. Paquinimod treatment not only reduces the clinical severity of dry eye symptoms but also diminishes the inflammatory response associated with Th17 cells. This pathway’s inhibition leads to decreased levels of pro-inflammatory cytokines and a reduction in the activation of pathogenic immune responses (Wei et al., 2025).

Recent studies highlight the beneficial effects of S100A8/A9 blockade, which include a marked reduction in ocular discomfort and improvement in tear production in SjDED patients. The modulation of the Acod1/STAT3 signaling pathway may also enhance the efficacy of existing therapies, indicating a synergistic potential when combined with conventional immunosuppressive treatments (Liang et al., 2024).

Role of Immune Cells in Sjögren’s Dry Eye Disease Pathogenesis

The immune dysregulation observed in SjDED is primarily driven by the infiltration and activation of various immune cell types, including Th17 cells, DCs, and macrophages. The upregulation of S100A8/A9 facilitates the recruitment and activation of these immune cells, promoting a local inflammatory environment conducive to tissue damage.

Th17 cells are known to produce IL-17, a cytokine that exacerbates inflammation and contributes to the pathogenesis of autoimmune diseases, including SjDED. The sustained presence of these cells, likely stimulated by S100A8/A9, reinforces the autoimmune response, creating a cycle of inflammation that perpetuates dry eye symptoms (Wei et al., 2025).

Innovative Strategies for Managing Sjögren’s Dry Eye Disease

To address the challenges posed by SjDED, innovative strategies focusing on the modulation of immune responses are being developed. These approaches aim to restore balance to the immune system by targeting the S100A8/A9/Acod1/STAT3 pathway and inhibiting Th17 cell activity.

S100A8/A9 Inhibitors: Agents like paquinimod have shown promise in preclinical models and are now being evaluated for clinical efficacy in human trials.
Biologic Therapies: Targeting specific cytokines involved in the inflammatory process, such as IL-6 and IL-23, can provide a tailored approach to therapy that may yield better results than traditional immunosuppressants.
Combined Modality Approaches: Incorporating S100A8/A9 inhibitors with other treatments, such as corticosteroids or anti-inflammatory drugs, may enhance therapeutic outcomes by addressing multiple pathways in the disease process (Wei et al., 2025).
Patient Education and Support: Improving awareness among patients and healthcare providers regarding the significance of early diagnosis and treatment can lead to better management of SjDED.

Conclusion

The S100A8/A9 complex plays a critical role in the pathogenesis of Sjögren’s dry eye disease by promoting Th17 cell responses and driving local inflammation. Targeting this pathway offers promising therapeutic potential to alleviate symptoms and improve quality of life for patients suffering from this chronic condition. As research continues to advance in this area, the development of more effective treatment modalities may soon be on the horizon.

FAQ Section

What is Sjögren’s dry eye disease?

Sjögren’s dry eye disease is an autoimmune disorder characterized by inflammation of the lacrimal glands, leading to decreased tear production and dry eyes.

How do S100A8/A9 proteins affect SjDED?

S100A8/A9 proteins promote the differentiation of Th17 cells through dendritic cells, enhancing inflammatory responses and worsening dry eye symptoms.

What are the therapeutic options for SjDED?

Therapeutic options include S100A8/A9 inhibitors like paquinimod, biologic therapies targeting specific cytokines, and combined modality approaches, including corticosteroids.

Why is early diagnosis important for SjDED?

Early diagnosis is crucial as it allows for timely intervention, which can prevent the progression of the disease and improve patient outcomes.

Can lifestyle changes help manage SjDED?

Yes, lifestyle changes such as maintaining hydration, using humidifiers, and avoiding irritants can help alleviate symptoms.

References

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Wei, Y., et al. (2025). S100A8/A9 promotes dendritic cell-mediated Th17 cell response in Sjögren’s dry eye disease by regulating the Acod1/STAT3 pathway. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11737457/
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