Role of cannabinoids and vitamin E analogues in macrophages foam cells formation

Abstract

Recently, macrophages foam cells have gained attention in cases of electronic‐cigarette or vaping product use‐associated lung injury (EVALI). An increased number of foam cells was detected in bronchoalveolar lavages and lungs after inhaling e‐cigarette smoke from products containing cannabinoids and the vitamin E analogue, alpha‐tocopherol acetate (αTA), that was present as vape‐cartridge additive. Increased levels of intact αTA are reportedly detected in EVALI indicating that conversion of αTA to αT may less occur in lungs upon inhaling vapors from e‐cigarettes containing αTA.HypothesisWhereas the molecular mechanisms by which macrophages foam cells are formed after vaping are unclear, it appears possible that cannabinoid receptors play a role, as lung‐resident macrophages express cannabinoid receptors. Dysregulation of cannabinoid receptors by αTA and cannabinoids may induce the CD36 scavenger receptor/fatty acids transporter (CD36/FAT) and/or reduce the ATP binding cassette transporters A1 and G1 (ABCA1/G1) expression leading to lipid accumulation. Therefore, we analyzed the regulatory effects on lipid homeostasis of natural alpha‐tocopherol (RRR‐αT), natural RRR‐αTA (αTAn) and synthetic racemic all‐rac‐αTA (αTAr) with and without co‐treatment with cannabinoids (cannabinol (CBD), Δ9‐tetrahydrocannabinol (THC)) in THP‐1 monocytes and macrophages (differentiated for 48 h with 100 ng/ml phorbol‐12‐myristate‐13‐acetate (PMA)).ResultsQuantification of lipids in macrophages indicated that more lipids accumulate with αT, less with αTAn and αTAr, whereas control alpha‐tocopheryl phosphate (αTP) clearly inhibited. Co‐treatment with THC increased lipid accumulation with αT, αTAn as well as with CBD, whereas αTP again clearly inhibited. In THP‐1 monocytes, CD36 scavenger receptor was stimulated with αTAn and THC and with co‐treatment with THC and αTAn or CBD. In THP‐1 macrophages, CD36 was only up‐regulated by CBD and co‐treatment with αTAn or αTAr reduced it. In THP‐1 monocytes, cell cycle progression was only affected by CBD (increased G1, decreased S) and co‐treatment with αTAn and αTAr restored it. In macrophages, no significant toxicity was measured with lactate dehydrogenase (LDH) release assay by these treatments at 24 h, 48 h and 72 h at αTA concentrations below 50 μM.SummaryAlthough the mechanisms by which intact αTA may affect lungs in cases of EVALI are still unclear it may disrupt the pulmonary surfactant, act as linactant, and/or dysregulate lipid homeostasis and contribute to formation of macrophages foam cells and inflammation. Lipid accumulation in monocytes/macrophages and foam cells formation were modulated by cannabinoids and αTA but the involvement of lipid homeostasis genes such as CD36/FAT and ABCA1/G1 remains to be further elucidated. A detailed analysis of the molecular mechanisms by which foam cells are formed will not only be important to understand EVALI but also for atherosclerosis and non‐alcoholic steatohepatitis (NASH).