Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity
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.
Authors
- Robert Fürst (ORCID: https://orcid.org/0000-0002-9926-7578)
- Lena M. Berger (ORCID: https://orcid.org/0000-0002-7835-8067)
- Megan A. Palmer (ORCID: https://orcid.org/0000-0002-5188-792X)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Thomas Zech (ORCID: https://orcid.org/0009-0001-0911-2282)
- Andreas Weigert (ORCID: https://orcid.org/0000-0002-7529-1952)
- Dominik C. Fuhrmann (ORCID: https://orcid.org/0000-0002-4902-9387)
- Franz Bracher (ORCID: https://orcid.org/0000-0003-0009-8629)
- Anne Wolf (ORCID: https://orcid.org/0000-0003-2551-9821)
- Martin P. Schwalm (ORCID: https://orcid.org/0000-0002-1252-1829)
- Thomas Langmann (ORCID: https://orcid.org/0000-0001-6826-529X)
- Rolf Marschalek (ORCID: https://orcid.org/0000-0003-4870-3445)
- Luisa D. Burgers (ORCID: https://orcid.org/0000-0001-7504-1104)
- Gerd Geißlinger (ORCID: https://orcid.org/0000-0003-0552-7488)
- Robert Gurke (ORCID: https://orcid.org/0000-0001-8218-1295)
- Mohammed A.F. Elewa (ORCID: https://orcid.org/0000-0002-4633-5274)
- Dominique Thomas
- Mandy Hector
- Sarah Ciurus
Institutions
- Goethe University Frankfurt (DE)
- Kafrelsheikh University (EG)
- University of Cologne (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- University Hospital Cologne (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2025-02-22
- DOI
- https://doi.org/10.1007/s00018-025-05579-y
- Citations
- 3
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Ludwig-Maximilians-Universität München