(P30-036-25) Modulation of Inflammation and Cellular Lipid Homeostasis by Cannabinoids and Vitamin E Analogues in Human Macrophages

Objectives: Cannabinoids can bind to several cannabinoid receptors and modulate cellular signaling relevant for inflammation and lipid homeostasis. Likewise, several vitamin E analogues can modulate inflammatory signaling and foam cell formation in macrophages. We are investigating whether vitamin E analogues such as alpha-tocopherol acetate (αTA) can affect macrophages lipid accumulation and inflammation with and without co-treatment with cannabinoids.

Methods: We are analyzing the regulatory effects on the expression of genes involved in cellular lipid homeostasis (e.g., CD36/FAT, SRB1, FABP4/aP2, ABCA1/G1, PP2AC), inflammation (e.g., inflammatory cytokines, TNFα, IL1β, IL8, IL6) by natural alpha-tocopherol (RRR-αT), natural RRR-αTA (αTAn), synthetic racemic all-rac-αTA (αTAr) with/without co-treatment with cannabinoids (cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC)) in human THP-1 monocytes and macrophages.

Results: Our results suggest the induction of CD36/FAT mRNA expression after treatment with THC that can be prevented, albeit incompletely, by αTA or CBD. A similar response pattern was observed with PP2AC and genes involved in lipid efflux (ABCA1), but much less with SRB1, suggesting an imbalance between uptake, metabolism, and efflux of lipids/αTA increasing foam cell formation. Interestingly, genes involved in cellular lipid export (SRB1, ABCA1) were downregulated less by αTAn when compared to αTAr possibly as result of differentially forming a complex with THC. αTAr always inhibited more efficiently both lipid accumulation and the inflammatory response (TNFα, IL6) when compared to αTAn. In cells overexpressing CB1 we observed activation of NF_kB by THC that was inhibited by αTAr.

Conclusions: The inflammatory response of macrophages occurs as a result of tissue injury, infection and age-related degeneration. Cannabinoids and αTA may modulate the levels of inflammatory cytokines and lipids in macrophages by modulating signaling and gene expression via cannabinoid receptors.

Funding Sources: University of Miami Relief Funding Sponsored by the Office of the Vice Provost for Research+Scholarship (OVPRS) and the Office of Faculty Affairs (OFA) 12/13/2021/05-31/2022 “Regulatory effects of vitamin E analogues and cannabinoids on macrophages foam cells formation”