Cargando…
Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice
Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechan...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Hematology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900272/ https://www.ncbi.nlm.nih.gov/pubmed/34570880 http://dx.doi.org/10.1182/blood.2021011671 |
_version_ | 1784664080406020096 |
---|---|
author | Adams, Rachael C. Carter-Cusack, Dylan Shaikh, Samreen N. Llanes, Genesis T. Johnston, Rebecca L. Quaife-Ryan, Gregory Boyle, Glen Koufariotis, Lambros T. Möller, Andreas Blazar, Bruce R. Vukovic, Jana MacDonald, Kelli P. A. |
author_facet | Adams, Rachael C. Carter-Cusack, Dylan Shaikh, Samreen N. Llanes, Genesis T. Johnston, Rebecca L. Quaife-Ryan, Gregory Boyle, Glen Koufariotis, Lambros T. Möller, Andreas Blazar, Bruce R. Vukovic, Jana MacDonald, Kelli P. A. |
author_sort | Adams, Rachael C. |
collection | PubMed |
description | Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II(+) donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations. |
format | Online Article Text |
id | pubmed-8900272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-89002722022-03-07 Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice Adams, Rachael C. Carter-Cusack, Dylan Shaikh, Samreen N. Llanes, Genesis T. Johnston, Rebecca L. Quaife-Ryan, Gregory Boyle, Glen Koufariotis, Lambros T. Möller, Andreas Blazar, Bruce R. Vukovic, Jana MacDonald, Kelli P. A. Blood Transplantation Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II(+) donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations. American Society of Hematology 2022-03-03 /pmc/articles/PMC8900272/ /pubmed/34570880 http://dx.doi.org/10.1182/blood.2021011671 Text en © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. |
spellingShingle | Transplantation Adams, Rachael C. Carter-Cusack, Dylan Shaikh, Samreen N. Llanes, Genesis T. Johnston, Rebecca L. Quaife-Ryan, Gregory Boyle, Glen Koufariotis, Lambros T. Möller, Andreas Blazar, Bruce R. Vukovic, Jana MacDonald, Kelli P. A. Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title | Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title_full | Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title_fullStr | Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title_full_unstemmed | Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title_short | Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice |
title_sort | donor bone marrow–derived macrophage mhc ii drives neuroinflammation and altered behavior during chronic gvhd in mice |
topic | Transplantation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900272/ https://www.ncbi.nlm.nih.gov/pubmed/34570880 http://dx.doi.org/10.1182/blood.2021011671 |
work_keys_str_mv | AT adamsrachaelc donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT cartercusackdylan donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT shaikhsamreenn donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT llanesgenesist donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT johnstonrebeccal donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT quaiferyangregory donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT boyleglen donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT koufariotislambrost donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT mollerandreas donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT blazarbrucer donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT vukovicjana donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice AT macdonaldkellipa donorbonemarrowderivedmacrophagemhciidrivesneuroinflammationandalteredbehaviorduringchronicgvhdinmice |