MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION
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 reduced 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. Overall design: Cells were isolated from the brains of mice that were transplanted with Bone marrow (BM) alone or BM plus adjunctive spleen cells (GVHD). To delineate the inflammatory environment in the brain, scRNAseq was performed on the immune cells isolated from brains of BM and GVHD mice. To delineate the effect of CB2R expression on microglia and determine whether these cells had a more inflammatory signature, scRNAseq was performed on sorted micrglial cells obtained from brains of WT versus CB2R-/- GVHD recipient mice.