Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease

Alison Moe, Aditya Rayasam, Garrett Sauber, Ravi K. Shah, Ashley Doherty, Cheng Yin Yuan, Aniko Szabo, Bob M. Moore, Marco Colonna, Weiguo Cui, Julian Romero, Anthony E. Zamora, Cecilia J. Hillard, William R. Drobyski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere175205
JournalJournal of Clinical Investigation
Volume134
Issue number11
DOIs
StatePublished - Jun 3 2024

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease'. Together they form a unique fingerprint.

Cite this