Jankovic, Dragana and Ganesan, Jayanthi and Bscheider, Michael and Stickel, Natalie and Weber, Felix C. and Guarda, Greta and Follo, Marie and Pfeifer, Dietmar and Tardivel, Aubry and Ludigs, Kristina and Bouazzaoui, Abdellatif and Kerl, Katrin and Fischer, Julius C. and Haas, Tobias and Schmitt-Graeff, Annette and Manoharan, Anand and Mueller, Leonard and Finke, Juergen and Martin, Stefan F. and Gorka, Oliver and Peschel, Christian and Ruland, Juergen and Idzko, Marco and Duyster, Justus and Holler, Ernst and French, Lars E. and Poeck, Hendrik and Contassot, Emmanuel and Zeiser, Robert (2013) The Nlrp3 inflammasome regulates acute graft-versus-host disease. JOURNAL OF EXPERIMENTAL MEDICINE, 210 (10). pp. 1899-1910. ISSN 0022-1007, 1540-9538
Full text not available from this repository. (Request a copy)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-1 beta production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1 beta 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-1 beta cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1 beta 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-1 beta 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CD4(+) T-CELLS; ROR-GAMMA-T; URIC-ACID; RAPAMYCIN INHIBITION; NALP3 INFLAMMASOME; MAMMALIAN TARGET; DENDRITIC CELLS; GVHD; TRANSPLANTATION; IMMUNITY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2020 12:00 |
| Last Modified: | 31 Mar 2020 12:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16019 |
Actions (login required)
 |
View Item |
