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Background <p>Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is marked by Th2-type inflammation and defective regulatory T (Treg) cell function, with unclear upstream regulatory mechanisms. Nemo-like kinase (NLK), a conserved serine/threonine kinase involved in immune regulation, has an uncharacterized role in ECRSwNP.</p> Objective <p>This study aimed to investigate the involvement of NLK in the pathogenesis of ECRSwNP, particularly its association with Treg/Th2 imbalance.</p> Results <p>Clinical sample analyses (immunohistochemistry, RT-qPCR, Western blot) showed that NLK was specifically downregulated in ECRSwNP tissues, with expression negatively correlated with Th2 cytokines (IL-4, IL-5, IL-13), eosinophil marker ECP, and disease severity, but positively correlated with Treg cell quantity and function. Co-immunoprecipitation and in vitro kinase assays revealed that NLK directly phosphorylated Foxp3 at 7 conserved sites (such as S19, T341), inhibiting STUB1-mediated K48-type ubiquitination via steric hindrance to stabilize Foxp3. NLK knockdown impaired Treg suppression of PBMC proliferation, increased Th2 cell proportion, and upregulated Th2 cytokines, forming a pathological cascade of reduced NLK, destabilized Foxp3, defective Treg function, and excessive Th2 inflammation.</p> Conclusion <p>NLK acts as a critical hub regulating Treg/Th2 balance in ECRSwNP by stabilizing Foxp3 through phosphorylation-dependent inhibition of STUB1-mediated ubiquitination.</p>

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Nemo-like kinase enhances immunosuppressive activity of CD4+CD25+Foxp3+ Treg cells in eosinophilic chronic rhinosinusitis through phosphorylation-mediated Foxp3 protein stabilization

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Ying Wang,
  • Wei Ma,
  • Li Xu,
  • Jie Lu,
  • Bin Zhu,
  • Qi Yan,
  • Bing Guan

摘要

Background

Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is marked by Th2-type inflammation and defective regulatory T (Treg) cell function, with unclear upstream regulatory mechanisms. Nemo-like kinase (NLK), a conserved serine/threonine kinase involved in immune regulation, has an uncharacterized role in ECRSwNP.

Objective

This study aimed to investigate the involvement of NLK in the pathogenesis of ECRSwNP, particularly its association with Treg/Th2 imbalance.

Results

Clinical sample analyses (immunohistochemistry, RT-qPCR, Western blot) showed that NLK was specifically downregulated in ECRSwNP tissues, with expression negatively correlated with Th2 cytokines (IL-4, IL-5, IL-13), eosinophil marker ECP, and disease severity, but positively correlated with Treg cell quantity and function. Co-immunoprecipitation and in vitro kinase assays revealed that NLK directly phosphorylated Foxp3 at 7 conserved sites (such as S19, T341), inhibiting STUB1-mediated K48-type ubiquitination via steric hindrance to stabilize Foxp3. NLK knockdown impaired Treg suppression of PBMC proliferation, increased Th2 cell proportion, and upregulated Th2 cytokines, forming a pathological cascade of reduced NLK, destabilized Foxp3, defective Treg function, and excessive Th2 inflammation.

Conclusion

NLK acts as a critical hub regulating Treg/Th2 balance in ECRSwNP by stabilizing Foxp3 through phosphorylation-dependent inhibition of STUB1-mediated ubiquitination.