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Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome

Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However,...

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Autores principales: Stackowicz, Julien, Gaudenzio, Nicolas, Serhan, Nadine, Conde, Eva, Godon, Ophélie, Marichal, Thomas, Starkl, Philipp, Balbino, Bianca, Roers, Axel, Bruhns, Pierre, Jönsson, Friederike, Moguelet, Philippe, Georgin-Lavialle, Sophie, Broderick, Lori, Hoffman, Hal M., Galli, Stephen J., Reber, Laurent L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421266/
https://www.ncbi.nlm.nih.gov/pubmed/34477811
http://dx.doi.org/10.1084/jem.20201466
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author Stackowicz, Julien
Gaudenzio, Nicolas
Serhan, Nadine
Conde, Eva
Godon, Ophélie
Marichal, Thomas
Starkl, Philipp
Balbino, Bianca
Roers, Axel
Bruhns, Pierre
Jönsson, Friederike
Moguelet, Philippe
Georgin-Lavialle, Sophie
Broderick, Lori
Hoffman, Hal M.
Galli, Stephen J.
Reber, Laurent L.
author_facet Stackowicz, Julien
Gaudenzio, Nicolas
Serhan, Nadine
Conde, Eva
Godon, Ophélie
Marichal, Thomas
Starkl, Philipp
Balbino, Bianca
Roers, Axel
Bruhns, Pierre
Jönsson, Friederike
Moguelet, Philippe
Georgin-Lavialle, Sophie
Broderick, Lori
Hoffman, Hal M.
Galli, Stephen J.
Reber, Laurent L.
author_sort Stackowicz, Julien
collection PubMed
description Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
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spelling pubmed-84212662022-04-04 Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome Stackowicz, Julien Gaudenzio, Nicolas Serhan, Nadine Conde, Eva Godon, Ophélie Marichal, Thomas Starkl, Philipp Balbino, Bianca Roers, Axel Bruhns, Pierre Jönsson, Friederike Moguelet, Philippe Georgin-Lavialle, Sophie Broderick, Lori Hoffman, Hal M. Galli, Stephen J. Reber, Laurent L. J Exp Med Brief Definitive Report Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology. Rockefeller University Press 2021-09-03 /pmc/articles/PMC8421266/ /pubmed/34477811 http://dx.doi.org/10.1084/jem.20201466 Text en © 2021 Stackowicz et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Stackowicz, Julien
Gaudenzio, Nicolas
Serhan, Nadine
Conde, Eva
Godon, Ophélie
Marichal, Thomas
Starkl, Philipp
Balbino, Bianca
Roers, Axel
Bruhns, Pierre
Jönsson, Friederike
Moguelet, Philippe
Georgin-Lavialle, Sophie
Broderick, Lori
Hoffman, Hal M.
Galli, Stephen J.
Reber, Laurent L.
Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title_full Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title_fullStr Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title_full_unstemmed Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title_short Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome
title_sort neutrophil-specific gain-of-function mutations in nlrp3 promote development of cryopyrin-associated periodic syndrome
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421266/
https://www.ncbi.nlm.nih.gov/pubmed/34477811
http://dx.doi.org/10.1084/jem.20201466
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