The effect of cholesterol on macrophage-foam-cell generation upon zymosan-induced inflammation in mice

It has been shown that a significant number (about 40% of the total population) of macrophage-foam cells (MFCs) are formed during the early period (24 h) of zymosan-induced peritonitis resolution. Agonists of peroxisome proliferator-activated receptors α, γ (PPAR-α, γ) exert an anti-inflammatory effect, preventing its formation (Dushkin et al., 2007). The work is devoted to the influence of cholesterol-containing liposomes (CHLs) on the dynamics of zymosan-induced peritonitis in C57Bl/6 mice. Cholesterol accumulation, cytokine production, PPAR-γ activity, and cholesterol efflux in macrophages have been assayed. Infiltration of neutrophils, mononuclears, and increased MFC number in the peritonel cavity of zymosan-induced mice enhanced the inflammation process and MFC resolution period. Macrophages obtained after zymosan injection preferentially accumulated triglycerides (TGs) incorporated into TG, whereas CHLs at zymosan-induced inflammation promoted utilization of the [1-¹⁴C]oleate pool in cholesterol ethers (maximum after 2 days) and reduction of fluorescent NBD-cholesterol efflux from macrophages during the whole inflammation period. Cholesterol efflux after zymosan exposure was inhibited for 1–2 days, restored after 3 days, and enhanced at the fifth day. CHLs stimulated TNF-α and TGF-β1 production but inhibited IL-10 production and PPAR-γ DNA-binding activity in macrophages at early stages of zymosan-induced peritonitis. Thus, accumulation of cholesterol in inflammatory macrophages and MFC generation prolong the resolution of acute inflammation changing the balance of pro- and anti-inflammatory cytokins and inhibiting PPAR-γ activity and cholesterol efflux.