Abstract
The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.
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Acknowledgements
This work was supported by the Austrian Science Fund (FWF) project P25642-B22, DOC 32-B28 and the Special Research Program SFB-F6101, SFB-F6105 and SFB-F6106. AL is supported by the Deutsche Forschungsgemeinschaft (Heisenberg-Professorship, project number 24141047). We thank Marion Bokor for histological sample preparation, immunohistochemical staining and help with RT-qPCRs, Bettina Tutzer and Sara Lang for their help with in vivo experiments and Claus Vogl for help with the statistical analysis.
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Poelzl, A., Lassnig, C., Tangermann, S. et al. TYK2 licenses non-canonical inflammasome activation during endotoxemia. Cell Death Differ 28, 748–763 (2021). https://doi.org/10.1038/s41418-020-00621-x
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DOI: https://doi.org/10.1038/s41418-020-00621-x
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