Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease. J Clin Invest 2024 Apr 25;134(11)
Date
04/25/2024Pubmed ID
38662453Pubmed Central ID
PMC11142740DOI
10.1172/JCI175205Scopus ID
2-s2.0-85195012384 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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.
Author List
Moe A, Rayasam A, Sauber G, Shah RK, Doherty A, Yuan CY, Szabo A, Moore BM 2nd, Colonna M, Cui W, Romero J, Zamora AE, Hillard CJ, Drobyski WRAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinCecilia J. Hillard PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Alison Moe Research Scientist II in the Medicine department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AllograftsAnimals
Disease Models, Animal
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Male
Mice
Mice, Knockout
Microglia
Receptor, Cannabinoid, CB2
T-Lymphocytes
