Cholesterol membrane content has a ubiquitous evolutionary function in immune cell activation the role of HDLBonacina, Fabriziaa; Pirillo, Angelab,c; Catapano, Alberico L.a,c; Norata, Giuseppe D.a,bCurrent Opinion in Lipidology: December 2019 - Volume 30 - Issue 6 - p 462–469 doi: 10.1097/MOL.0000000000000642 THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. Watts Buy Abstract Author InformationAuthors Article MetricsMetrics Purpose of review Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes. Recent findings The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach. Summary Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology. aDepartment of Pharmacological and Biomolecular Sciences, University of Milan bCenter for the Study of Atherosclerosis, E. Bassini Hospital cIRCCS MultiMedica, Milan, Italy Correspondence to Giuseppe D. Norata, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy. E-mail: firstname.lastname@example.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.