Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.
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.
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2].
Lukas
L
Schwab
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany. [3].
Luise
L
Goroncy
1] Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. [2] Division of Bone Marrow Transplantation, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA. [3].
Senthilnathan
S
Palaniyandi
1] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany. [2] Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany. [3] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany.
Sanjivan
S
Gautam
Center of Chronic Immunodeficiency, Albert-Ludwigs-University Freiburg, Germany.
Antigoni
A
Triantafyllopoulou
Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
Attila
A
Mocsai
Department of Radiology Medical Physics, University Medical Center, Freiburg, Germany.
Wilfried
W
Reichardt
Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.
Fridrik J
FJ
Karlsson
1] Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. [2] Division of Bone Marrow Transplantation, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
Sabarinath V
SV
Radhakrishnan
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
Kathrin
K
Hanke
Department of Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
Annette
A
Schmitt-Graeff
1] Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [2] Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University Freiburg, Germany.
Marina
M
Freudenberg
Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
Friederike D
FD
von Loewenich
Department of Urology, University Medical Center, Freiburg, Germany.
Philipp
P
Wolf
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
Franziska
F
Leonhardt
Department of Radiology Medical Physics, University Medical Center, Freiburg, Germany.
Nicoleta
N
Baxan
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Dietmar
D
Pfeifer
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Oliver
O
Schmah
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Anne
A
Schönle
Allergy Research Group, Department of Dermatology, University Medical Center, University Freiburg, Germany.
Stefan F
SF
Martin
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Roland
R
Mertelsmann
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Justus
J
Duyster
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
Jürgen
J
Finke
1] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [2] Department of Neuropathology, University Medical Center, Freiburg, Germany.
Marco
M
Prinz
1] Center of Chronic Immunodeficiency, Albert-Ludwigs-University Freiburg, Germany. [2] Center for Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
Philipp
P
Henneke
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Hans
H
Häcker
1] Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. [2] Division of Bone Marrow Transplantation, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA. [3].
Gerhard C
GC
Hildebrandt
1] Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany. [2] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [3].
Georg
G
Häcker
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [3] Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University Freiburg, Germany. [4].
Robert
R
Zeiser
D000818:Animals; D002066:Busulfan; D003520:Cyclophosphamide; D005434:Flow Cytometry; D005620:Freund's Adjuvant; D006086:Graft vs Host Disease / Q000276:immunology* / Q000503:physiopathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006652:Histological Techniques; D007082:Ileum / Q000276:immunology* / Q000382:microbiology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008156:Luciferases; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D064307:Microbiota / Q000276:immunology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009504:Neutrophils / Q000276:immunology*; D009195:Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D003520:Cyclophosphamide; D005620:Freund's Adjuvant; D009195:Peroxidase; D008156:Luciferases; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002066:Busulfan