Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever

PLoS Biol. 2022 Nov 7;20(11):e3001351. doi: 10.1371/journal.pbio.3001351. eCollection 2022 Nov.

Abstract

Pyrin is a cytosolic immune sensor that nucleates an inflammasome in response to inhibition of RhoA by bacterial virulence factors, triggering the release of inflammatory cytokines, including IL-1β. Gain-of-function mutations in the MEFV gene encoding Pyrin cause autoinflammatory disorders, such as familial Mediterranean fever (FMF) and Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). To precisely define the role of Pyrin in pathogen detection in human immune cells, we compared initiation and regulation of the Pyrin inflammasome response in monocyte-derived macrophages (hMDM). Unlike human monocytes and murine macrophages, we determined that hMDM failed to activate Pyrin in response to known Pyrin activators Clostridioides difficile (C. difficile) toxins A or B (TcdA or TcdB), as well as the bile acid analogue BAA-473. The Pyrin inflammasome response was enabled in hMDM by prolonged priming with either LPS or type I or II interferons and required an increase in Pyrin expression. Notably, FMF mutations lifted the requirement for prolonged priming for Pyrin activation in hMDM, enabling Pyrin activation in the absence of additional inflammatory signals. Unexpectedly, in the absence of a Pyrin response, we found that TcdB activated the NLRP3 inflammasome in hMDM. These data demonstrate that regulation of Pyrin activation in hMDM diverges from monocytes and highlights its dysregulation in FMF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins*
  • Clostridioides difficile*
  • Familial Mediterranean Fever* / genetics
  • Familial Mediterranean Fever* / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Macrophages / metabolism
  • Mice
  • Mutation
  • Pyrin / genetics
  • Pyrin / metabolism

Substances

  • Pyrin
  • Inflammasomes
  • trimethylaminocarboxyldihydroboran
  • Bacterial Toxins
  • MEFV protein, human

Grants and funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 369799452 (TRR237) (E.L.), Project-ID 414786233 (SFB1403) (E.L.), Project ID 432325352 (SFB1454) (E.L.), DFG (GE1017/5-1) (R.G) and Germany’s Excellence Strategy – ImmunoSensation2 – Project-ID 390873048 (EXC2151) (E.L.), The work was also supported by the Helmholtz Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' (ZT-0027) (E.L.) and the German-Israeli Foundation for Scientific Research and Development, Grant No: 1085 (V.H.) This project was partially funded by the Niedersächsiches Ministerium für Wissenschaft und Kultur (MWK), Niedersächsisches Vorab [grant number ZN3380] (K.H.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.