Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft versus host disease. J Clin Invest 2024 Apr 25
Date
04/25/2024Pubmed ID
38662453DOI
10.1172/JCI175205Abstract
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 which 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 has 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 Ii BM, Colonna M, Cui W, Romero J, Zamora AE, Hillard CJ, Drobyski WRAuthors
Alison Moe PhD Research Scientist II in the Medicine department at Medical College of WisconsinAnthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
