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

J Clin Invest. 2024 Apr 25;134(11):e175205. doi: 10.1172/JCI175205.

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.

Keywords: Bone marrow transplantation; Immunotherapy; Neuroscience; Transplantation.

MeSH terms

  • Allografts
  • Animals
  • Disease Models, Animal
  • Graft vs Host Disease* / genetics
  • Graft vs Host Disease* / immunology
  • Graft vs Host Disease* / metabolism
  • Graft vs Host Disease* / pathology
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Male
  • Mice
  • Mice, Knockout
  • Microglia* / immunology
  • Microglia* / metabolism
  • Microglia* / pathology
  • Neuroinflammatory Diseases* / immunology
  • Neuroinflammatory Diseases* / metabolism
  • Neuroinflammatory Diseases* / pathology
  • Receptor, Cannabinoid, CB2* / genetics
  • Receptor, Cannabinoid, CB2* / immunology
  • Receptor, Cannabinoid, CB2* / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Cnr2 protein, mouse
  • Receptor, Cannabinoid, CB2