Valerio Chiurchiù1, Mirko Lanuti2, Giuseppina Catanzaro2, Filomena Fezza3, Cinzia Rapino4, Mauro Maccarrone5. 1. European Center for Brain Research (CERC)/I.R.C.C.S. Santa Lucia Foundation, Rome, Italy; Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy. Electronic address: v.chiurchiu@hsantalucia.it. 2. European Center for Brain Research (CERC)/I.R.C.C.S. Santa Lucia Foundation, Rome, Italy; Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy. 3. European Center for Brain Research (CERC)/I.R.C.C.S. Santa Lucia Foundation, Rome, Italy; Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy. 4. Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy. 5. European Center for Brain Research (CERC)/I.R.C.C.S. Santa Lucia Foundation, Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy. Electronic address: m.maccarrone@unicampus.it.
Abstract
OBJECTIVE: Cannabinoid receptors are activated in murine macrophages upon exposure to oxidized low-density lipoproteins (oxLDL), and type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis, because it promotes cholesterol accumulation and release of inflammatory mediators. Conversely, accumulated evidence suggests a protective role for type-2 cannabinoid receptor (CB2R). Here, we sought to ascertain whether different elements of the endocannabinoid system (ECS) were activated in human lipid-laden macrophages, and whether CB2R played any role in atherogenesis and inflammation of these cells. METHODS AND RESULTS: Human macrophages were exposed to oxLDL in order to obtain lipid-laden foam cells. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the production of the endocannabinoids in both macrophages and foam cells, and radiometric assays were performed to measure cannabinoid receptor binding and activity of endocannabinoid metabolizing enzymes. OxLDL accumulation was investigated by confocal imaging, and cytokine production and release were measured by means of flow cytometry and ELISA. The results showed that human macrophages possess a fully functional ECS, which was modulated by oxLDL. Selective CB2R activation reduced cellular oxLDL accumulation, which was associated with decreased expression of CD36 scavenger receptor, and decreased production of TNFα, IL-12 and IL-10. These anti-atherogenic and anti-inflammatory effects were reverted by the selective CB2R antagonist SR144528. CONCLUSIONS: A fully active ECS is present in human macrophages and macrophage-derived foam cells. Selective activation of CB2R reduces CD36-dependent oxLDL accumulation and modulates production of inflammatory cytokines, thus representing a potential therapeutic strategy to combat atherosclerosis.
OBJECTIVE: Cannabinoid receptors are activated in murine macrophages upon exposure to oxidized low-density lipoproteins (oxLDL), and type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis, because it promotes cholesterol accumulation and release of inflammatory mediators. Conversely, accumulated evidence suggests a protective role for type-2 cannabinoid receptor (CB2R). Here, we sought to ascertain whether different elements of the endocannabinoid system (ECS) were activated in humanlipid-laden macrophages, and whether CB2R played any role in atherogenesis and inflammation of these cells. METHODS AND RESULTS:Human macrophages were exposed to oxLDL in order to obtain lipid-laden foam cells. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the production of the endocannabinoids in both macrophages and foam cells, and radiometric assays were performed to measure cannabinoid receptor binding and activity of endocannabinoid metabolizing enzymes. OxLDL accumulation was investigated by confocal imaging, and cytokine production and release were measured by means of flow cytometry and ELISA. The results showed that human macrophages possess a fully functional ECS, which was modulated by oxLDL. Selective CB2R activation reduced cellular oxLDL accumulation, which was associated with decreased expression of CD36 scavenger receptor, and decreased production of TNFα, IL-12 and IL-10. These anti-atherogenic and anti-inflammatory effects were reverted by the selective CB2R antagonist SR144528. CONCLUSIONS: A fully active ECS is present in human macrophages and macrophage-derived foam cells. Selective activation of CB2R reduces CD36-dependent oxLDL accumulation and modulates production of inflammatory cytokines, thus representing a potential therapeutic strategy to combat atherosclerosis.
Authors: Irene M Wohlman; Gabriella M Composto; Diane E Heck; Ned D Heindel; C Jeffrey Lacey; Christophe D Guillon; Robert P Casillas; Claire R Croutch; Donald R Gerecke; Debra L Laskin; Laurie B Joseph; Jeffrey D Laskin Journal: Toxicol Appl Pharmacol Date: 2016-04-26 Impact factor: 4.219
Authors: Mariana Macedo de Almeida; Camilla P Dias-Rocha; Clara F Reis-Gomes; Haimei Wang; Aline Cordeiro; Carmen C Pazos-Moura; Lisa Joss-Moore; Isis H Trevenzoli Journal: Eur J Nutr Date: 2020-07-15 Impact factor: 5.614