Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis

Abstract

Background and aims: Cholesterol crystal (CC)-induced inflammation is a critical step in the development of atherosclerosis. CCs activate the complement system and induce an inflammatory response resulting in phagocytosis of the CCs, production of reactive oxygen species (ROS) and release of cytokines. The cyclodextrin 2-hydroxypropyl-β-cyclodextrin has been found to reduce CC-induced complement activation and induce regression of established atherosclerotic plaques in a mouse model of atherosclerosis, thus inhibition of complement with cyclodextrins is a potential new strategy for treatment of inflammation during atherosclerosis. We hypothesized that other cyclodextrins, like α-cyclodextrin, may have related functions. Methods: The effect of cyclodextrins on CC-induced complement activation, phagocytosis, and production of ROS from granulocytes and monocytes was investigated by flow cytometry and ELISA. Results: We showed that α-cyclodextrin strongly inhibits CC-induced complement activation by inhibiting binding of the pattern recognition molecules C1q (via IgM) and ficolin-2. The reduced CC-induced complement activation mediated by α-cyclodextrin resulted in reduced phagocytosis and reduced ROS production in monocytes and granulocytes. Alpha-cyclodextrin was the most effective inhibitor of CC-induced complement activation, with the reduction in deposition of complement activation products being significantly different from the reduction induced by 2hydroxypropyl-β-cyclodextrin. We also found that α-cyclodextrin was able to dissolve CCs. Conclusions: This study identified α-cyclodextrin as a potential candidate in the search for therapeutics to prevent CC-induced inflammation in atherosclerosis.

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

“…The time-dependent findings are also in line with experiments reported by Pilely et al . and Ding et al ., that show that while incubation of different types of cyclodextrin for a short period of time (10 and 30 min) is anti-inflammatory ( 35 ), incubation for 24 and 48hr lead to ototoxicity ( 19 ). Together, these observations indicate that while CD has potential in advantageously depleting cellular cholesterol, it is essential to monitor the quantity of cellular cholesterol and adjust the therapeutic dose/time accordingly to prevent undesired pro-inflammatory side-effects.…”

Cyclodextrin Monomers and Polymers for Drug Activity Enhancement

“…It has been demonstrated that Mβ-CD and HPβ-CD reduce cholesterol accumulation [ 26 , 27 , 28 , 29 ]. Pilely et al, in 2019 discovered that α-CD and HPβ-CD can solubilize cholesterol crystals, reducing the complement-mediated inflammation by binding of C1q (via IgM) and ficolin-2 to cholesterol crystals, which resulted in reduced phagocytosis and reduced ROS production [ 30 ]. Moreover, different derivatives such as HPγ-CD (which cannot complex cholesterol) mobilize cholesterol; the treatment with HPγ-CD and HPβ-CD [ 31 ] induced the expression of protein-like LAMP-1, which is expressed in the lysosomal membrane.…”

Cyclic Oligosaccharides as Active Drugs, an Updated Review

“…Pilely et al, in 2019, discovered that α-CD inhibits cholesterol crystal-induced complement-mediated inflammation better than HPβ-CD. It is even able to solubilize cholesterol crystals [ 65 ].…”