Oral Presentation Australasian Cytometry Society 41st Annual Conference

The Effects Of Colchicine On In Vitro And In Vivo Models Of Atherosclerosis (24243)

Nisha Schwarz 1 , Sanuja Fernando 1 2 , Thalia Skoumbourdis 1 , Catherine Dimasi 1 , Anna Williamson 1 2 , Deborah F. Toledo 1 , Belinda A. Di Bartolo 1 2 , Joanne Tan 1 2 , Christina A. Bursill 1 2 , Stephen J. Nicholls 1 2 , Peter J. Psaltis 1 2
  1. South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  2. Medicine, University of Adelaide, Adelaide, South Australia, Australia

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 and in vivo effects of colchicine on macrophage biology 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 10nM 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 48h with oxLDL (p<0.0002) or CC (p<0.01). This inhibition of foam cell formation was not associated with down-regulation of scavenger receptor expression, but rather with reduced phagocytic capacity of BMDMs (p<0.002), and increased total cholesterol efflux capacity (3-fold, p<0.05). Colchicine also attenuated CC-induced upregulation of genes and proteins associated with the NLRP3 inflammasome (Nlrp3, Caspase-1, Il1b). In vivo, ApoE-/- mice fed a high cholesterol diet for 16 weeks and orally gavaged with a clinical dose of colchicine daily for 12 weeks, showed reduction in aortic atherosclerosis by >45% compared to placebo group (placebo 17.8%±2.0% vs colchicine 8.7%± 1.1%, p<0.0004).

 

Conclusion: These novel results indicate that colchicine inhibits oxLDL and CC-induced foam cell formation, most likely via effects on phagocytosis and cholesterol efflux of macrophages. In addition, it effectively inhibits both priming and activation of the NLRP3 inflammasome. In vivo, clinical dose of colchicine showed reduced disease burden indicating a novel role in reducing atherosclerosis.