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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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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. |
format | Online Article Text |
id | pubmed-3782050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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