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The Nlrp3 inflammasome regulates acute graft-versus-host disease

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning t...

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Autores principales: Jankovic, Dragana, Ganesan, Jayanthi, Bscheider, Michael, Stickel, Natalie, Weber, Felix C., Guarda, Greta, Follo, Marie, Pfeifer, Dietmar, Tardivel, Aubry, Ludigs, Kristina, Bouazzaoui, Abdellatif, Kerl, Katrin, Fischer, Julius C., Haas, Tobias, Schmitt-Gräff, Annette, Manoharan, Anand, Müller, Leonard, Finke, Jürgen, Martin, Stefan F., Gorka, Oliver, Peschel, Christian, Ruland, Jürgen, Idzko, Marco, Duyster, Justus, Holler, Ernst, French, Lars E., Poeck, Hendrik, Contassot, Emmanuel, Zeiser, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782050/
https://www.ncbi.nlm.nih.gov/pubmed/23980097
http://dx.doi.org/10.1084/jem.20130084
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author Jankovic, Dragana
Ganesan, Jayanthi
Bscheider, Michael
Stickel, Natalie
Weber, Felix C.
Guarda, Greta
Follo, Marie
Pfeifer, Dietmar
Tardivel, Aubry
Ludigs, Kristina
Bouazzaoui, Abdellatif
Kerl, Katrin
Fischer, Julius C.
Haas, Tobias
Schmitt-Gräff, Annette
Manoharan, Anand
Müller, Leonard
Finke, Jürgen
Martin, Stefan F.
Gorka, Oliver
Peschel, Christian
Ruland, Jürgen
Idzko, Marco
Duyster, Justus
Holler, Ernst
French, Lars E.
Poeck, Hendrik
Contassot, Emmanuel
Zeiser, Robert
author_facet Jankovic, Dragana
Ganesan, Jayanthi
Bscheider, Michael
Stickel, Natalie
Weber, Felix C.
Guarda, Greta
Follo, Marie
Pfeifer, Dietmar
Tardivel, Aubry
Ludigs, Kristina
Bouazzaoui, Abdellatif
Kerl, Katrin
Fischer, Julius C.
Haas, Tobias
Schmitt-Gräff, Annette
Manoharan, Anand
Müller, Leonard
Finke, Jürgen
Martin, Stefan F.
Gorka, Oliver
Peschel, Christian
Ruland, Jürgen
Idzko, Marco
Duyster, Justus
Holler, Ernst
French, Lars E.
Poeck, Hendrik
Contassot, Emmanuel
Zeiser, Robert
author_sort Jankovic, Dragana
collection PubMed
description The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome–mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro–IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication.
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spelling pubmed-37820502014-03-23 The Nlrp3 inflammasome regulates acute graft-versus-host disease Jankovic, Dragana Ganesan, Jayanthi Bscheider, Michael Stickel, Natalie Weber, Felix C. Guarda, Greta Follo, Marie Pfeifer, Dietmar Tardivel, Aubry Ludigs, Kristina Bouazzaoui, Abdellatif Kerl, Katrin Fischer, Julius C. Haas, Tobias Schmitt-Gräff, Annette Manoharan, Anand Müller, Leonard Finke, Jürgen Martin, Stefan F. Gorka, Oliver Peschel, Christian Ruland, Jürgen Idzko, Marco Duyster, Justus Holler, Ernst French, Lars E. Poeck, Hendrik Contassot, Emmanuel Zeiser, Robert J Exp Med Brief Definitive Report The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome–mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro–IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication. The Rockefeller University Press 2013-09-23 /pmc/articles/PMC3782050/ /pubmed/23980097 http://dx.doi.org/10.1084/jem.20130084 Text en © 2013 Jankovic et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Jankovic, Dragana
Ganesan, Jayanthi
Bscheider, Michael
Stickel, Natalie
Weber, Felix C.
Guarda, Greta
Follo, Marie
Pfeifer, Dietmar
Tardivel, Aubry
Ludigs, Kristina
Bouazzaoui, Abdellatif
Kerl, Katrin
Fischer, Julius C.
Haas, Tobias
Schmitt-Gräff, Annette
Manoharan, Anand
Müller, Leonard
Finke, Jürgen
Martin, Stefan F.
Gorka, Oliver
Peschel, Christian
Ruland, Jürgen
Idzko, Marco
Duyster, Justus
Holler, Ernst
French, Lars E.
Poeck, Hendrik
Contassot, Emmanuel
Zeiser, Robert
The Nlrp3 inflammasome regulates acute graft-versus-host disease
title The Nlrp3 inflammasome regulates acute graft-versus-host disease
title_full The Nlrp3 inflammasome regulates acute graft-versus-host disease
title_fullStr The Nlrp3 inflammasome regulates acute graft-versus-host disease
title_full_unstemmed The Nlrp3 inflammasome regulates acute graft-versus-host disease
title_short The Nlrp3 inflammasome regulates acute graft-versus-host disease
title_sort nlrp3 inflammasome regulates acute graft-versus-host disease
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782050/
https://www.ncbi.nlm.nih.gov/pubmed/23980097
http://dx.doi.org/10.1084/jem.20130084
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