The Nlrp3 inflammasome regulates acute graft-versus-host disease.
Détails
Etat: Public
Version: de l'auteur⸱e
ID Serval
serval:BIB_1FFE4D66E5D6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The Nlrp3 inflammasome regulates acute graft-versus-host disease.
Périodique
Journal of Experimental Medicine
ISSN
1540-9538 (Electronic)
ISSN-L
0022-1007
Statut éditorial
Publié
Date de publication
2013
Volume
210
Numéro
10
Pages
1899-1910
Langue
anglais
Résumé
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.
Pubmed
Web of science
Open Access
Oui
Création de la notice
01/11/2013 10:26
Dernière modification de la notice
20/08/2019 13:55