The Nlrp3 inflammasome regulates acute graft-versus-host disease

Author:

Jankovic Dragana1,Ganesan Jayanthi22,Bscheider Michael3,Stickel Natalie222,Weber Felix C.2,Guarda Greta4,Follo Marie2,Pfeifer Dietmar2,Tardivel Aubry4,Ludigs Kristina4,Bouazzaoui Abdellatif5,Kerl Katrin1,Fischer Julius C.3,Haas Tobias3,Schmitt-Gräff Annette2,Manoharan Anand4,Müller Leonard2,Finke Jürgen2,Martin Stefan F.2,Gorka Oliver3,Peschel Christian3,Ruland Jürgen3,Idzko Marco2,Duyster Justus2,Holler Ernst5,French Lars E.1,Poeck Hendrik3,Contassot Emmanuel1,Zeiser Robert222

Affiliation:

1. Department of Dermatology, University Hospital, CH-8091 Zürich, Switzerland

2. Department of Hematology and Oncology, Department of Pneumology, Allergy Research Group, Department of Dermatology, and Department of Pathology, University Medical Center Freiburg; Faculty of Biology; Spemann Graduate School of Biology and Medicine (SGBM), and Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University, 79085 Freiburg, Germany

3. III. Medizinische Klinik, Klinikum Rechts der Isar and Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, 80333 München, Germany

4. Biochemistry Institute, University of Lausanne, CH-1066 Epalinges, Switzerland

5. Department of Hematology and Oncology, University Hospital Regensburg, 93052 Regensburg, Germany

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3