The CB₁ Receptor Differentially Regulates IFN-γ Production In Vitro and in Experimental Autoimmune Encephalomyelitis

Introduction: Activation of the peripheral immune system and the infiltration of immune cells into the central nervous system are both key features of the experimental autoimmune encephalomyelitis (EAE) model. By exploring how the endocannabinoid system works to modulate this response, we can better understand how exogenous cannabinoids, such as THC, might be used to modulate the immune responses of multiple sclerosis patients. Materials and Methods: In this study, we examined the role of the CB₁ receptor in IFN-γ and IL-17A production in the EAE model and in vitro stimulations of naive splenocytes using Cnr1 mice and wild-type (WT) littermates. We also introduce a novel method of scoring spinal cord histological sections to show the differences in disease severity between Cnr1 and WT mice with EAE. Results: Clinical scores of Cnr1EAE and WT/EAE mice showed more severe disease progression in Cnr1 mice, which was confirmed using our new histological scoring method. In the peripheral immune system, IFN-γ production by restimulated splenocytes from Cnr1/EAE mice, compared with WT/EAE mice, was increased and the primary source of IFN-γ was a CD3^- cell population; however, IFN-γ production by Cnr1 splenocytes was decreased compared with WT splenocytes when the primary source of IFN-γ was CD3⁺ T cells in cultures from naive mice stimulated by either anti-CD3/anti-CD28 antibodies or Staphylococcal superantigens. Conclusion: These findings suggest a duality to the CB₁ receptor's effects on the peripheral immune response, which varies based on the specific cell types stimulated. Knowledge of the complex nature of a receptor is an important part of determining its potential usefulness as a therapeutic target, and these findings further define the role of CB₁ in IFN-γ responses.