The Mechanism by Which Cannabidiol (CBD) Suppresses TNF-α Secretion Involves Inappropriate Localization of TNF-α Converting Enzyme (TACE)

Overview

Journal Cell Immunol

Publisher Elsevier

Specialties Allergy & Immunology
Cell Biology

Date 2024 Jan 21

PMID 38245915

Authors

Christa M Frodella

Liyuan Liu

Wei Tan

Stephen B Pruett

Barbara L F Kaplan

Affiliations

Soon will be listed here.

Abstract

Cannabidiol (CBD) is a phytocannabinoid derived from Cannabis sativa that exerts anti-inflammatory mechanisms. CBD is being examined for its putative effects on the neuroinflammatory disease, multiple sclerosis (MS). One of the major immune mediators that propagates MS and its mouse model experimental autoimmune encephalomyelitis (EAE) are macrophages. Macrophages can polarize into an inflammatory phenotype (M1) or an anti-inflammatory phenotype (M2a). Therefore, elucidating the impact on macrophage polarization with CBD pre-treatment is necessary to understand its anti-inflammatory mechanisms. To study this effect, murine macrophages (RAW 264.7) were pre-treated with CBD (10 µM) or vehicle (ethanol 0.1 %) and were either left untreated (naive; cell media only), or stimulated under M1 (IFN-γ + lipopolysaccharide, LPS) or M2a (IL-4) conditions for 24 hr. Cells were analyzed for macrophage polarization markers, and supernatants were analyzed for cytokines and chemokines. Immunofluorescence staining was performed on M1-polarized cells for the metalloprotease, tumor necrosis factor-α-converting enzyme (TACE), as this enzyme is responsible for the secretion of TNF-α. Overall results showed that CBD decreased several markers associated with the M1 phenotype while exhibiting less effects on the M2a phenotype. Significantly, under M1 conditions, CBD increased the percentage of intracellular and surface TNF-α but decreased secreted TNF-α. This phenomenon might be mediated by TACE as staining showed that CBD sequestered TACE intracellularly. CBD also prevented RelA nuclear translocation. These results suggest that CBD may exert its anti-inflammatory effects by reducing M1 polarization and decreasing TNF-α secretion via inappropriate localization of TACE and RelA.

References

Sonar S, Lal G . The iNOS Activity During an Immune Response Controls the CNS Pathology in Experimental Autoimmune Encephalomyelitis. Front Immunol. 2019; 10:710. PMC: 6458273. DOI: 10.3389/fimmu.2019.00710. View

Brambilla R, Ashbaugh J, Magliozzi R, Dellarole A, Karmally S, Szymkowski D . Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain. 2011; 134(Pt 9):2736-54. PMC: 3170538. DOI: 10.1093/brain/awr199. View

Yekhtin Z, Khuja I, Meiri D, Or R, Almogi-Hazan O . Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model. Biomedicines. 2022; 10(8). PMC: 9332744. DOI: 10.3390/biomedicines10081793. View

Kaltschmidt C, Kaltschmidt B, Lannes-Vieira J, Kreutzberg G, Wekerle H, Baeuerle P . Transcription factor NF-kappa B is activated in microglia during experimental autoimmune encephalomyelitis. J Neuroimmunol. 1994; 55(1):99-106. DOI: 10.1016/0165-5728(94)90151-1. View

Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T . Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 2010; 49(7):1215-28. PMC: 2886310. DOI: 10.1093/rheumatology/keq031. View

Falvo J, Tsytsykova A, Goldfeld A . Transcriptional control of the TNF gene. Curr Dir Autoimmun. 2010; 11:27-60. PMC: 4785889. DOI: 10.1159/000289196. View

Liu L, Stokes J, Tan W, Pruett S . An optimized flow cytometry panel for classifying macrophage polarization. J Immunol Methods. 2022; 511:113378. DOI: 10.1016/j.jim.2022.113378. View

Grell M, Wajant H, Zimmermann G, Scheurich P . The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci U S A. 1998; 95(2):570-5. PMC: 18461. DOI: 10.1073/pnas.95.2.570. View

Wajant H, Scheurich P . TNFR1-induced activation of the classical NF-κB pathway. FEBS J. 2011; 278(6):862-76. DOI: 10.1111/j.1742-4658.2011.08015.x. View

10.

Calligaris M, Cuffaro D, Bonelli S, Spano D, Rossello A, Nuti E . Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution. Molecules. 2021; 26(4). PMC: 7916773. DOI: 10.3390/molecules26040944. View

11.

Li M, Xu B, Li X, Li Y, Qiu S, Chen K . Mitofusin 2 confers the suppression of microglial activation by cannabidiol: Insights from in vitro and in vivo models. Brain Behav Immun. 2022; 104:155-170. DOI: 10.1016/j.bbi.2022.06.003. View

12.

Baker D, Butler D, Scallon B, ONeill J, Turk J, Feldmann M . Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins. Eur J Immunol. 1994; 24(9):2040-8. DOI: 10.1002/eji.1830240916. View

13.

Yeisley D, Arabiyat A, Hahn M . Cannabidiol-Driven Alterations to Inflammatory Protein Landscape of Lipopolysaccharide-Activated Macrophages May Be Mediated by Autophagy and Oxidative Stress. Cannabis Cannabinoid Res. 2021; 6(3):253-263. PMC: 8217602. DOI: 10.1089/can.2020.0109. View

14.

Preteroti M, Traboulsi H, Greiss P, Lapohos O, Fonseca G, Eidelman D . Receptor-mediated effects of Δ -tetrahydrocannabinol and cannabidiol on the inflammatory response of alveolar macrophages. Immunol Cell Biol. 2022; 101(2):156-170. DOI: 10.1111/imcb.12614. View

15.

Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R . Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol. 2011; 163(7):1507-19. PMC: 3165959. DOI: 10.1111/j.1476-5381.2011.01379.x. View

16.

Grajchen E, Hendriks J, Bogie J . The physiology of foamy phagocytes in multiple sclerosis. Acta Neuropathol Commun. 2018; 6(1):124. PMC: 6240956. DOI: 10.1186/s40478-018-0628-8. View

17.

Lisi S, DAmore M, Sisto M . ADAM17 at the interface between inflammation and autoimmunity. Immunol Lett. 2014; 162(1 Pt A):159-69. DOI: 10.1016/j.imlet.2014.08.008. View

18.

Charbonneau M, Harper K, Grondin F, Pelmus M, McDonald P, Dubois C . Hypoxia-inducible factor mediates hypoxic and tumor necrosis factor alpha-induced increases in tumor necrosis factor-alpha converting enzyme/ADAM17 expression by synovial cells. J Biol Chem. 2007; 282(46):33714-33724. DOI: 10.1074/jbc.M704041200. View

19.

Nichols J, Kummari E, Sherman J, Yang E, Dhital S, Gilfeather C . CBD Suppression of EAE Is Correlated with Early Inhibition of Splenic IFN-γ + CD8+ T Cells and Modest Inhibition of Neuroinflammation. J Neuroimmune Pharmacol. 2020; 16(2):346-362. PMC: 7679272. DOI: 10.1007/s11481-020-09917-8. View

20.

Nichols J, Kaplan B . Immune Responses Regulated by Cannabidiol. Cannabis Cannabinoid Res. 2020; 5(1):12-31. PMC: 7173676. DOI: 10.1089/can.2018.0073. View