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ResearchIn-Press PreviewNeuroscienceTransplantation Open Access | 10.1172/JCI175205
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Moe, A. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Rayasam, A. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Shah, R. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Doherty, A. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Yuan, C. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
Find articles by Szabo, A. in: JCI | PubMed | Google Scholar
1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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1Department of Medicine, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, United States of America
3Division of Biostatistics, Medical College of Wisconsin, Milwaukee, United States of America
4Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, United States of America
5Department of Pathology and Immunology, Washington University, St. Louis, United States of America
6Department of Pathology, Northwestern University, Chicago, United States of America
7Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
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Published April 25, 2024 - More info
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.