Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage

Lukas Schwab, Luise Goroncy, Senthilnathan Palaniyandi, Sanjivan Gautam, Antigoni Triantafyllopoulou, Attila Mocsai, Wilfried Reichardt, Fridrik J. Karlsson, Sabarinath V. Radhakrishnan, Kathrin Hanke, Annette Schmitt-Graeff, Marina Freudenberg, Friederike D. Von Loewenich, Philipp Wolf, Franziska Leonhardt, Nicoleta Baxan, Dietmar Pfeifer, Oliver Schmah, Anne Schönle, Stefan F. MartinRoland Mertelsmann, Justus Duyster, Jürgen Finke, Marco Prinz, Philipp Henneke, Hans Häcker, Gerhard C. Hildebrandt, Georg Häcker, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

Abstract

Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.

Original languageEnglish
Pages (from-to)648-654
Number of pages7
JournalNature Medicine
Volume20
Issue number6
DOIs
StatePublished - Jun 2014

Bibliographical note

Funding Information:
This study was supported by the Deutsche Jose Carreras Leukämie Stiftung (DJCLS grant # R12/11), Deutsche Forschungsgemeinschaft (DFG), Germany, Heisenberg Professorship to R.Z. (DFG ZE 872/3-1) and DFG individual grant to R.Z. (DFG ZE 872/1-2), in part by SFB 850 (to R.Z.), Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School to R.Z. and G.H. and BIOSS II, project no. B13 to R.Z.), Deutsche Krebshilfe (to R.Z.), and Marie Curie FP7-IRG268390 (to A.T.) and also in part by the IDEA 2012 award (LSU Health Sciences Center, to G.C.H.). A.M. was funded by the European Research Council and the Wellcome Trust. H.H. was supported by the American Lebanese Syrian Associated Charities (ALSAC). We thank M. Follo for proofreading the manuscript.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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