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

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...

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Autores principales: Mangan, Matthew S. J., Gorki, Friederike, Krause, Karoline, Heinz, Alexander, Pankow, Anne, Ebert, Thomas, Jahn, Dieter, Hiller, Karsten, Hornung, Veit, Maurer, Marcus, Schmidt, Florian I., Gerhard, Ralf, Latz, Eicke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671422/
https://www.ncbi.nlm.nih.gov/pubmed/36342970
http://dx.doi.org/10.1371/journal.pbio.3001351
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author Mangan, Matthew S. J.
Gorki, Friederike
Krause, Karoline
Heinz, Alexander
Pankow, Anne
Ebert, Thomas
Jahn, Dieter
Hiller, Karsten
Hornung, Veit
Maurer, Marcus
Schmidt, Florian I.
Gerhard, Ralf
Latz, Eicke
author_facet Mangan, Matthew S. J.
Gorki, Friederike
Krause, Karoline
Heinz, Alexander
Pankow, Anne
Ebert, Thomas
Jahn, Dieter
Hiller, Karsten
Hornung, Veit
Maurer, Marcus
Schmidt, Florian I.
Gerhard, Ralf
Latz, Eicke
author_sort Mangan, Matthew S. J.
collection PubMed
description 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.
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spelling pubmed-96714222022-11-18 Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever Mangan, Matthew S. J. Gorki, Friederike Krause, Karoline Heinz, Alexander Pankow, Anne Ebert, Thomas Jahn, Dieter Hiller, Karsten Hornung, Veit Maurer, Marcus Schmidt, Florian I. Gerhard, Ralf Latz, Eicke PLoS Biol Research Article 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. Public Library of Science 2022-11-07 /pmc/articles/PMC9671422/ /pubmed/36342970 http://dx.doi.org/10.1371/journal.pbio.3001351 Text en © 2022 Mangan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mangan, Matthew S. J.
Gorki, Friederike
Krause, Karoline
Heinz, Alexander
Pankow, Anne
Ebert, Thomas
Jahn, Dieter
Hiller, Karsten
Hornung, Veit
Maurer, Marcus
Schmidt, Florian I.
Gerhard, Ralf
Latz, Eicke
Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title_full Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title_fullStr Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title_full_unstemmed Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title_short Transcriptional licensing is required for Pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial Mediterranean fever
title_sort transcriptional licensing is required for pyrin inflammasome activation in human macrophages and bypassed by mutations causing familial mediterranean fever
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671422/
https://www.ncbi.nlm.nih.gov/pubmed/36342970
http://dx.doi.org/10.1371/journal.pbio.3001351
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