Anti-inflammatory mechanisms of cannabinoids: an immunometabolic perspective
A number of studies have implicated cannabinoids as potent anti-inflammatory mediators. However, the exact mechanism by which cannabinoids exert these effects remains to be fully explained. The recent resurgence in interest regarding the metabolic adaptations undergone by activated immune cells has highlighted the intricate connection between metabolism and an inflammatory phenotype. In this regard, evidence suggests that cannabinoids may alter cell metabolism by increasing AMPK activity. In turn, emerging evidence suggests that the activation of AMPK by cannabinoids may mediate an anti-inflammatory effect through a range of processes. First, AMPK may promote oxidative metabolism, which have been shown to play a central role in immune cell polarisation towards a tolerogenic phenotype. AMPK activation may also attenuate anabolic processes which in turn may antagonise immune cell function. Furthermore, AMPK activity promotes the induction of autophagy, which in turn may promote anti-inflammatory effects through various well-described processes. Taken together, these observations implicate cannabinoids to mediate part of their anti-inflammatory effects through alterations in immune cell metabolism and the induction of autophagy.
KeywordsInflammation Cannabinoid Autoimmune Immunometabolism Autophagy AMPK
The authors would like to thank Leo Kruger for his valuable discussion. The authors acknowledge funding support from the Cancer Association of South Africa (CANSA), National Research Foundation (NRF), and the South African Medical Research Council (SAMRC).
- Bátkai S, Mukhopadhyay P, Horváth B et al (2012) Δ 8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB 2 receptors. Br J Pharmacol 165:2450–2461. https://doi.org/10.1111/j.1476-5381.2011.01410.x CrossRefGoogle Scholar
- Fukuzumi M, Shinomiya H, Shimizu Y et al (1996) Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT 1. Infect Immun 64:108–112Google Scholar
- Gimenez-Roqueplo AP, Favier J, Rustin P et al (2001) The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 69:1186–1197. https://doi.org/10.1086/324413 CrossRefGoogle Scholar
- Inoki K, Kim J, Guan K-L (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381–400. https://doi.org/10.1146/annurev-pharmtox-010611-134537 CrossRefGoogle Scholar
- Mathison JC, Ulevitch RJ (1979) The clearance, tissue distribution, and cellular localization of intravenously injected lipopolysaccharide in rabbits. J Immunol (Baltimore, Md 1950) 123:2133–2143Google Scholar
- Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763Google Scholar
- Yang L, Rozenfeld R, Wu D et al (2014) Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free Radic Biol Med 68:260–267. https://doi.org/10.1016/j.freeradbiomed.2013.12.026 CrossRefGoogle Scholar