Abstract
Cannabidiol (CBD) is a bioactive compound isolated from Cannabis plants that has garnered attention within the medical community due to its potent anti-inflammatory properties. To better understand how CBD limits excessive neuroinflammation we administered CBD via oral gavage (20 mg/kg) in a murine model of multiple sclerosis (MS) known as experimental autoimmune encephalomyelitis (EAE). Using single cell RNA sequencing (scRNA Seq) and array-based transcriptomics we were able to delineate how CBD limits excessive inflammation within the central nervous system (CNS) as well as within the intestinal lining in EAE. In-depth scRNA Seq analysis of CNS tissue demonstrated that CBD treatment resulted in a significant reduction in CXCL9, CXCL10 and IL-1β expression within the CNS, leading to inhibited infiltration of inflammatory macrophages. CBD inhibited IL-1β production independent of the classical cannabinoid receptors, CB1 and CB2. CBD treatment also led to induction of Myeloid-derived Suppressor Cells (MDSCs) both in the CNS and periphery. Interestingly, CBD treatment of EAE mice revealed significant suppression of inflammation in the gastrointestinal (GI) tract. The intestinal epithelial cells (IECs) of CBD treated mice demonstrated a transcriptional inhibition of a family of pyroptosis initiators that drive localized inflammation known as gasdermins (GSDMs). Further investigation into the GI tract via 16s sequencing of cecal and fecal contents demonstrated that oral administration of CBD resulted in no significant changes in the intestinal microbiota composition. These findings demonstrate the beneficial effect of CBD treatment on autoimmune neuroinflammation by ablating expression of pro-inflammatory chemoattractants, regulating inflammatory macrophage activity, promoting MDSC expansion, and limiting the systemic low-grade inflammation in the GI tract, culminating in the attenuation of EAE.
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Data Availability
The datasets presented in this study can be found in online repositories hosted via https://www.ncbi.nlm.nih.gov/ under the bioproject numbers PRJNA745189 (16s) and PRJNA (scRNA Seq).
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This work was supported in part by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788 and R01AI123947. The graphical abstract for this manuscript was created using Biorender.com
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ND, PN, and MN conceived the hypotheses and ideas conveyed throughout the entirety of this manuscript. Sample collection was performed by ND, BLH, KW, and KM. Analysis on data collected was performed by ND. ND wrote the manuscript and developed the accompanying figures with aid from PN and MN.
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Dopkins, N., Miranda, K., Wilson, K. et al. Effects of Orally Administered Cannabidiol on Neuroinflammation and Intestinal Inflammation in the Attenuation of Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 17, 15–32 (2022). https://doi.org/10.1007/s11481-021-10023-6
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DOI: https://doi.org/10.1007/s11481-021-10023-6