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<p>Chronic inflammatory diseases are a significant global burden and are associated with dysregulated resolution of inflammation. Therefore, promoting the process of resolution is a promising therapeutic approach. This study presents the potent anti-inflammatory and pro-resolving effects of a natural product-derived compound called C81. Administration of C81 in a therapeutic window resolved inflammation in the murine imiquimod-induced psoriasis model, and reduced microglial infiltration in a laser-induced choroidal neovascularisation model. Investigations into the underlying mechanisms of C81 identified the DYRK1B/STAT3 axis as a new regulator of inflammatory processes in leukocytes. The inhibition of DYRK1B by C81 resulted in attenuated STAT3 phosphorylation. The depletion of STAT3-regulated gene expression led to the inhibition of leukocyte adhesion and migration due to reduced integrin activation, and in addition to the inhibition of the release of pro-inflammatory mediators such as cytokines and eicosanoids. Importantly, the pro-resolving effects of C81 included the cell type-specific induction of apoptosis in neutrophils and a subsequent increase in efferocytosis. In conclusion, we report the DYRK1B/STAT3 axis as a novel and promising therapeutic target for activating the resolution of inflammation.</p> Graphical Abstract <p></p>

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Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月22日

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  • Sarah Ciurus,
  • Mohammed A. F. Elewa,
  • Megan A. Palmer,
  • Anne Wolf,
  • Mandy Hector,
  • Dominik C. Fuhrmann,
  • Dominique Thomas,
  • Robert Gurke,
  • Martin P. Schwalm,
  • Lena Berger,
  • Thomas J. Zech,
  • Luisa D. Burgers,
  • Rolf Marschalek,
  • Gerd Geisslinger,
  • Stefan Knapp,
  • Thomas Langmann,
  • Franz Bracher,
  • Andreas Weigert,
  • Robert Fürst

摘要

Chronic inflammatory diseases are a significant global burden and are associated with dysregulated resolution of inflammation. Therefore, promoting the process of resolution is a promising therapeutic approach. This study presents the potent anti-inflammatory and pro-resolving effects of a natural product-derived compound called C81. Administration of C81 in a therapeutic window resolved inflammation in the murine imiquimod-induced psoriasis model, and reduced microglial infiltration in a laser-induced choroidal neovascularisation model. Investigations into the underlying mechanisms of C81 identified the DYRK1B/STAT3 axis as a new regulator of inflammatory processes in leukocytes. The inhibition of DYRK1B by C81 resulted in attenuated STAT3 phosphorylation. The depletion of STAT3-regulated gene expression led to the inhibition of leukocyte adhesion and migration due to reduced integrin activation, and in addition to the inhibition of the release of pro-inflammatory mediators such as cytokines and eicosanoids. Importantly, the pro-resolving effects of C81 included the cell type-specific induction of apoptosis in neutrophils and a subsequent increase in efferocytosis. In conclusion, we report the DYRK1B/STAT3 axis as a novel and promising therapeutic target for activating the resolution of inflammation.

Graphical Abstract