In:
PLOS Biology, Public Library of Science (PLoS), Vol. 20, No. 11 ( 2022-11-7), p. e3001351-
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001351
DOI:
10.1371/journal.pbio.3001351.g001
DOI:
10.1371/journal.pbio.3001351.g002
DOI:
10.1371/journal.pbio.3001351.g003
DOI:
10.1371/journal.pbio.3001351.g004
DOI:
10.1371/journal.pbio.3001351.g005
DOI:
10.1371/journal.pbio.3001351.g006
DOI:
10.1371/journal.pbio.3001351.g007
DOI:
10.1371/journal.pbio.3001351.s001
DOI:
10.1371/journal.pbio.3001351.s002
DOI:
10.1371/journal.pbio.3001351.s003
DOI:
10.1371/journal.pbio.3001351.s004
DOI:
10.1371/journal.pbio.3001351.s005
DOI:
10.1371/journal.pbio.3001351.s006
DOI:
10.1371/journal.pbio.3001351.s007
DOI:
10.1371/journal.pbio.3001351.s008
DOI:
10.1371/journal.pbio.3001351.r001
DOI:
10.1371/journal.pbio.3001351.r002
DOI:
10.1371/journal.pbio.3001351.r003
DOI:
10.1371/journal.pbio.3001351.r004
DOI:
10.1371/journal.pbio.3001351.r005
DOI:
10.1371/journal.pbio.3001351.r006
DOI:
10.1371/journal.pbio.3001351.r007
DOI:
10.1371/journal.pbio.3001351.r008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2126773-X
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