title: A Novel Function for P2Y2 in Myeloid Recipient-Derived Cells during Graft-versus-Host Disease.
abstract: Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. During the initiation phase of acute GvHD, endogenous danger signals such as ATP are released and inform the innate immune system via activation of the purinergic receptor P2X7 that a noninfectious damage has occurred. A second ATP-activated purinergic receptor involved in inflammatory diseases is P2Y2. In this study, we used P2y2(-/-) mice to test the role of this receptor in GvHD. P2y2(-/-) recipients experienced reduced GvHD-related mortality, IL-6 levels, enterocyte apoptosis, and histopathology scores. Chimeric mice with P2y2 deficiency restricted to hematopoietic tissues survived longer after GvHD induction than did wild-type mice. P2y2 deficiency of the recipient was connected to lower levels of myeloperoxidase in the intestinal tract of mice developing GvHD and a reduced myeloid cell signature. Selective deficiency of P2Y2 in inflammatory monocytes decreased GvHD severity. Mechanistically, P2y2(-/-) inflammatory monocytes displayed defective ERK activation and reactive oxygen species production. Compatible with a role of P2Y2 in human GvHD, the frequency of P2Y2(+) cells in inflamed GvHD lesions correlated with histopathological GvHD severity. Our findings indicate a novel function for P2Y2 in ATP-activated recipient myeloid cells during GvHD, which could be exploited when targeting danger signals to prevent GvHD.
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Verena
authors.initials: V
authors.lastname: Klämbt
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Wohlfeil
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Lukas
authors.initials: L
authors.lastname: Schwab
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Hülsdünker
authors.affiliation: Department of Pneumology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Korcan
authors.identifier: http://orcid.org/0000-0001-7043-6692
authors.initials: K
authors.lastname: Ayata
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Petya
authors.initials: P
authors.lastname: Apostolova
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Heide
authors.initials: H
authors.lastname: Dierbach
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Gabriele
authors.identifier: http://orcid.org/0000-0002-8263-5768
authors.initials: G
authors.lastname: Prinz
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.affiliation: Institute of Neuropathology, University Medical Center Freiburg, 79106 Freiburg, Germany; and BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Pneumology, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, 79104 Freiburg, Germany robert.zeiser@uniklinik-freiburg.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate