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

J Clin Immunol. 2023 Dec 22;44(1):8. doi: 10.1007/s10875-023-01621-5.

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.

Keywords: Autoinflammatory syndromes; FMF; Pyrin; inflammasome; pharmacological therapy.

Publication types

  • Review

MeSH terms

  • Familial Mediterranean Fever* / genetics
  • Humans
  • Inflammasomes / metabolism
  • Mevalonate Kinase Deficiency* / genetics
  • Mevalonate Kinase Deficiency* / therapy
  • Pyoderma Gangrenosum*
  • Pyrin / genetics
  • Syndrome

Substances

  • Inflammasomes
  • Pyrin
  • MEFV protein, human