Autophagy Enhancers Regulate Cholesterol-Induced Cytokine Secretion and Cytotoxicity in Macrophages.

Objective: Hypercholesterolaemia transforms macrophages into lipid-laden foam cells in circulation, which can activate the immune response. Compromised autophagy and inflammatory cytokines are involved in the pathogenesis and progression of metabolic diseases. The aim of this study was to identify the role of autophagy as a modulator of the inflammatory response and cytotoxicity in macrophages under hypercholesterolaemic conditions. Methods: High cholesterol-induced cytokine secretion and alteration of autophagy-associated molecules were confirmed by cytokine array and western blot analysis, respectively. To confirm whether autophagic regulation affects high cholesterol-induced cytokine release and cytotoxicity, protein levels of autophagic molecules, cell viability, and cytotoxicity were measured in cultured macrophages treated autophagy enhancers. Results: Cholesterol treatment increased cytokine secretion, cellular toxicity, and lactate dehydrogenase release in lipopolysaccharide (LPS)-primed macrophages. Concomitantly, altered levels of autophagy-related molecules were detected in LPS-primed macrophages under hypercholesterolaemic conditions. Treatment with autophagy enhancers reversed the secretion of cytokines, abnormally expressed autophagy-associated molecules, and cytotoxicity of LPS-primed macrophages. Conclusion: Autophagy enhancers inhibit inflammatory cytokine secretion and reduce cytotoxicity under metabolic disturbances, such as hypercholesterolaemia. Modulation of autophagy may be a novel approach to control the inflammatory response observed in metabolic diseases.