Anti-Inflammatory Effects of Colchicine on Oxidised Low-Density Lipoproteins and Cholesterol Crystal-Induced Macrophage Activation in vitro

Background: Macrophages are a major player in the inflammatory processes that underpin atherosclerosis. Colchicine is an inexpensive drug with broad anti-inflammatory activity and suspected benefits in coronary artery disease. Although it has been assumed that colchicine has anti-atherosclerotic potential, direct evidence for this is lacking. It is also unclear how colchicine influences inflammatory responses to atherogenic stimuli. Here we studied the in vitro effects of colchicine on macrophages with novel focus on macrophage responses to oxidised low-density lipoproteins (oxLDL) and cholesterol crystals (CC). Methods and Results: Based on initial dose titration studies and published literature, we used 10 nM colchicine to treat primary murine bone marrow-derived macrophages (BMDMs). At this concentration, colchicine did not affect BMDM viability, proliferation, differentiation or polarisation into M1 or M2 phenotypes. However, it reduced formation of Oil-Red-O+ foam cells by 30%, when BMDMs were incubated for 48 h with either oxLDL (p < 0.0002) or CC (p < 0.01). Interestingly, this inhibition of foam cell formation was not associated with down-regulation of scavenger receptor expression. Rather, colchicine reduced the phagocytic capacity of BMDMs by 2-fold, as determined by ingestion of PE-conjugated phagocytic beads (p < 0.002), and increased total cholesterol efflux capacity by 3-fold (p < 0.05), without altering efflux receptor expression. Finally, colchicine attenuated CC-induced upregulation of genes and proteins associated with the NLRP3 inflammasome (Nlrp3, Caspase-1, Il1β) Conclusion: These novel results indicate that colchicine inhibits oxLDL and CC-induced foam cell formation, most likely via effects on phagocytosis and cholesterol efflux. In addition, it effectively inhibits both priming and activation of the NLRP3 inflammasome.