The Nlrp3 inflammasome regulates acute graft-versus-host disease
Open Access
- 26 August 2013
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 210 (10), 1899-1910
- https://doi.org/10.1084/jem.20130084
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.This publication has 30 references indexed in Scilit:
- Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesisProceedings of the National Academy of Sciences of the United States of America, 2012
- IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cellsThe Journal of Experimental Medicine, 2012
- Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in miceBlood, 2011
- Graft-versus-host diseaseThe Lancet, 2009
- Alternative Activation of Macrophages: An Immunologic Functional PerspectiveAnnual Review of Immunology, 2009
- IL-17 contributes to CD4-mediated graft-versus-host diseaseBlood, 2009
- Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cellsThe Journal of Experimental Medicine, 2008
- Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cellsBlood, 2008
- Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activityBlood, 2007
- Toll-like receptor signallingNature Reviews Immunology, 2004