title: The Nlrp3 inflammasome regulates acute graft-versus-host disease.
abstract: 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.
authors: Department of Dermatology, University Hospital, CH-8091 Zürich, Switzerland.
authors: Dragana
authors: D
authors: Jankovic
authors: Jayanthi
authors: J
authors: Ganesan
authors: Michael
authors: M
authors: Bscheider
authors: Natalie
authors: N
authors: Stickel
authors: Felix C
authors: FC
authors: Weber
authors: Greta
authors: G
authors: Guarda
authors: Marie
authors: M
authors: Follo
authors: Dietmar
authors: D
authors: Pfeifer
authors: Aubry
authors: A
authors: Tardivel
authors: Kristina
authors: K
authors: Ludigs
authors: Abdellatif
authors: A
authors: Bouazzaoui
authors: Katrin
authors: K
authors: Kerl
authors: Julius C
authors: JC
authors: Fischer
authors: Tobias
authors: T
authors: Haas
authors: Annette
authors: A
authors: Schmitt-Gräff
authors: Anand
authors: A
authors: Manoharan
authors: Leonard
authors: L
authors: Müller
authors: Jürgen
authors: J
authors: Finke
authors: Stefan F
authors: SF
authors: Martin
authors: Oliver
authors: O
authors: Gorka
authors: Christian
authors: C
authors: Peschel
authors: Jürgen
authors: J
authors: Ruland
authors: Marco
authors: M
authors: Idzko
authors: Justus
authors: J
authors: Duyster
authors: Ernst
authors: E
authors: Holler
authors: Lars E
authors: LE
authors: French
authors: Hendrik
authors: H
authors: Poeck
authors: Emmanuel
authors: E
authors: Contassot
authors: Robert
authors: R
authors: Zeiser
mesh_terms: D000208:Acute Disease; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006086:Graft vs Host Disease / Q000209:etiology* / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D048069:Tumor Necrosis Factors / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D048069:Tumor Necrosis Factors; D020170:Caspase 1
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