Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease.
J Clin Invest
; 134(11)2024 Apr 25.
Article
em En
| MEDLINE
| ID: mdl-38662453
ABSTRACT
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
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Base de dados:
MEDLINE
Assunto principal:
Microglia
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Receptor CB2 de Canabinoide
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Doenças Neuroinflamatórias
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Doença Enxerto-Hospedeiro
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article