The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization.

Abstract

Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist SR141716A. Our study demonstrated that SR141716A accelerated the clinical onset and development of EAE, accompanied by body weight loss. SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and nuclear factor-kappaB/p65 (NF-κB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-α, IL-1β, IL-6) and chemokines (MCP-1, CX3CL1), accompanied by the shifts of cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-γ)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except chemokine CX3CL1. Consistently, SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-α, IL-1β, IL-6) while inhibited the production of IL-10 and chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of IL-4 and IL-10 were decreased while production of IL-17 and IFN-γ increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-κB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application.

• Authors: Zhi-Yin Lou, Jie Cheng, Xiao-Rong Wang, Yong-Fei Zhao, Jing Gan, Guo-Yu Zhou, Zhen-Guo Liu, Bao-Guo Xiao
• Journal: Journal of neuroimmunology (J Neuroimmunol) Vol. 317 Pg. 37-44 (04 15 2018) ISSN: 1872-8421 [Electronic] Netherlands
• PMID: 29501084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Cannabinoid Receptor Antagonists
• Receptor, Cannabinoid, CB1
• Rimonabant

Topics

• Animals
• Cannabinoid Receptor Antagonists (pharmacology)
• Cell Differentiation (physiology)
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism)
• Female
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, immunology, metabolism)
• Receptor, Cannabinoid, CB1 (immunology, metabolism)
• Rimonabant (pharmacology)