Inflammation. 2022 Mar 5. doi: 10.1007/s10753-022-01646-9. Online ahead of print.
Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kβ. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1-3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.