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Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes

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Abstract

Pyrin is a cytosolic protein encoded by the MEFV gene, predominantly expressed in innate immune cells. Upon activation, it forms an inflammasome, a multimolecular complex that enables the activation and secretion of IL-1β and IL-18. In addition, the Pyrin inflammasome activates Gasdermin D leading to pyroptosis, a highly pro-inflammatory cell death. Four autoinflammatory syndromes are associated with Pyrin inflammasome dysregulation: familial Mediterranean fever, hyper IgD syndrome/mevalonate kinase deficiency, pyrin-associated autoinflammation with neutrophilic dermatosis, and pyogenic arthritis, pyoderma gangrenosum, and acne syndrome. In this review, we discuss recent advances in understanding the molecular mechanisms regulating the two-step model of Pyrin inflammasome activation. Based on these insights, we discuss current pharmacological options and identify a series of existing molecules with therapeutic potential for the treatment of pyrin-associated autoinflammatory syndromes.

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Authors and Affiliations

  1. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, 3590, Diepenbeek, Belgium

    Flore Wouters, Jeroen Bogie & Jeroen van der Hilst

  2. University MS Center Hasselt, 3900, Pelt, Belgium

    Jeroen Bogie

  3. Department of Internal Medicine and Paediatrics, Ghent University, 9052, Ghent, Belgium

    Andy Wullaert

  4. VIB-UGent Center for Inflammation Research VIB, 9052, Ghent, Belgium

    Andy Wullaert

  5. Laboratory of Protein Science, Proteomics and Epigenetic Signalling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Andy Wullaert

  6. Department of Infectious Diseases and Immune Pathology, Jessa General Hospital and Limburg Clinical Research Center, Hasselt, Belgium

    Jeroen van der Hilst

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All authors contributed equally to this work. The first draft of the manuscript was written by FW and JvdH, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Wouters, F., Bogie, J., Wullaert, A. et al. Recent Insights in Pyrin Inflammasome Activation: Identifying Potential Novel Therapeutic Approaches in Pyrin-Associated Autoinflammatory Syndromes. J Clin Immunol 44, 8 (2024). https://doi.org/10.1007/s10875-023-01621-5

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