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

Abstract

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 CB 1 receptor in IFN-c and IL-17A production in the EAE model and in vitro stimulations of naive splenocytes using Cnr1 À/À 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 À/À and WT mice with EAE. Results: Clinical scores of Cnr1 À/À /EAE and WT/EAE mice showed more severe disease progression in Cnr1 À/À mice, which was confirmed using our new histological scoring method. In the peripheral immune system, IFN-c production by restimulated splenocytes from Cnr1 À/À /EAE mice, compared with WT/EAE mice, was increased and the primary source of IFN-c was a CD3 À cell population; however, IFN-c production by Cnr1 À/À splenocytes was decreased compared with WT splenocytes when the primary source of IFN-c 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 CB 1 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 CB 1 in IFN-c responses.

Bakuchiol and Ethyl (Linoleate/Oleate) Synergistically Modulate Endocannabinoid Tone in Keratinocytes and Repress Inflammatory Pathway mRNAs

“…This may reflect NF-κB inhibition, resulting in loss of TNF-driven PTGS2 expression ( Chen et al., 2000 ; Lin et al., 2004 ; Nakao et al., 2002 ). Third, BAK + ELN downregulated type I IFN pathway genes as seen previously for BAK ( Ma et al., 2017 ) and consistent with inhibition of IFN regulatory factors and IFN-γ production by eCB pathway activation ( Flannery et al., 2018 ; Nichols and Kaplan, 2021 ). These results suggest mechanisms by which BAK + ELN potentiates anti-inflammatory effects.…”

Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies

“…Furthermore, the treatment of EAE mice with rimonabant (CB 1 R antagonist) increased IFNγ production in spleen cells that were reactivated with MOG and other pro-inflammatory cytokines. These studies suggest the possibility of CB 1 R involvement in cytokine secretion (Nichols & Kaplan 2021 ).…”

Anti-inflammatory effects of recreational marijuana in virally suppressed youth with HIV-1 are reversed by use of tobacco products in combination with marijuana

“…Unique normalized DEG seen solely in the marijuana group included CCL5, CD274 (PDL-1), FAS, IFNγ, IL-15 and STAT1, genes in pro-inflammatory pathways known to be perturbed by HIV infection [ 50 – 56 ]. THC has an anti-CCL5 effect in SIV-infected rhesus macaques and Cannabis sativa is postulated to block signaling through Jak/Stat [ 57 – 59 ]. Our study is the first observation that marijuana may affect signaling through IL-15 and CD274 (PD-L1) in individuals with HIV.…”