Moe, AlisonRayasam, AdityaSauber, GarrettShah, Ravi K.Doherty, AshleyYuan, Cheng YinSzabo, AnikoMoore, Bob M.Colonna, MarcoCui, WeiguoRomero, JulianZamora, Anthony E.Hillard, Cecilia J.Drobyski, William R.2026-02-052026-02-052024-06-03Moe, A, Rayasam, A, Sauber, G, Shah, R K, Doherty, A, Yuan, C Y, Szabo, A, Moore, B M, Colonna, M, Cui, W, Romero, J, Zamora, A E, Hillard, C J & Drobyski, W R 2024, 'Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease', Journal of Clinical Investigation, vol. 134, no. 11, e175205. https://doi.org/10.1172/JCI1752050021-9738PubMedCentral: PMC11142740unpaywall: 10.1172/jci175205https://hdl.handle.net/10641/7840Publisher Copyright: © 2024, Moe et al.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.13127191enghttp://creativecommons.org/licenses/by-nc-nd/4.0/General MedicineJournal ArticleYesyesjournal articleopen access10.1172/JCI175205https://www.scopus.com/pages/publications/85195012384https://www.scopus.com/pages/publications/85195012384#tab=citedBy