Giambelluca S., Ochs M. and Lopez-Rodriguez E. BMC Biol. 2025;23(1):369.
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The role of cholesterol‑ and cholesterol crystal‑mediated inflammation has been extensively investi‑gated in circulating macrophages in the context of cardiovascular diseases while little is known about its contributionto lung diseases. However, lipid‑laden alveolar macrophages and crystal‑like structures have been reported in lungsof different human and animal models of lung diseases. In this study, we address the hypothesis that a mechanismof inflammasome activation, due to altered cholesterol metabolism, may occur also in alveolar macrophages.We tested the effect of soluble (cholesterol‑enriched liposomes) and crystalized cholesterol exposurein a cell model of macrophages and in primary murine alveolar macrophages. Both soluble and crystalized choles‑terol can be taken up by macrophages, mainly by phagocytosis for the crystals. Prolonged exposure to both formsof cholesterol leads to intracellular cholesterol accumulation in cytoplasmic lipid droplets and to foam cell forma‑tion in a time‑dependent manner. However, in unprimed alveolar macrophages, immunofluorescence detectionof the NLRP3 inflammasome and analysis of inflammatory cytokines showed that only cholesterol crystals stimulatethe assembly of the inflammasome in speck and release of IL‑18, indicating the sterile activation of the inflamma‑some. The role of NLRP3 was confirmed by chemical inhibition of the NLRP3 inflammasome in vitro and by validationin macrophages from NLRP3‑deficient mice.In alveolar macrophages, cholesterol crystals, but not soluble cholesterol, trigger the assembly and acti‑vation of the inflammasome, thus leading to the inflammasome‑dependent release of IL‑18. These results open newscenarios for the role of alveolar macrophages and of cholesterol‑mediated inflammation in the lung.
