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Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge., (© 2022 Bonacina et al.)

Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: Atherosclerosis is an inflammatory disorder of the arterial wall, in which several players contribute to the onset and progression of the disease. Besides the well-established role of lipids, specifically cholesterol, and immune cell activation, new insights on the molecular mechanisms underlying the atherogenic process have emerged., Recent Findings: Meta-inflammation, a condition of low-grade immune response caused by metabolic dysregulation, immunological memory of innate immune cells (referred to as "trained immunity"), cholesterol homeostasis in dendritic cells, and immunometabolism, i.e., the interplay between immunological and metabolic processes, have all emerged as new actors during atherogenesis. These observations reinforced the interest in directly targeting inflammation to reduce cardiovascular disease. The novel acquisitions in pathophysiology of atherosclerosis reinforce the tight link between lipids, inflammation, and immune response, and support the benefit of targeting LDL-C as well as inflammation to decrease the CVD burden. How this will translate into the clinic will depend on the balance between costs (monoclonal antibodies either to PCSK9 or to IL-1ß), side effects (increased incidence of death due to infections for anti-IL-1ß antibody), and the benefits for patients at high CVD risk.

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism. Highlights LAL is a checkpoint of intracellular lipid homeostasis that controls the amount of FC and FFAs released from the lysosome. LALD is characterized by massive accumulation of esterified cholesterol and triglycerides throughout the body, and in particular, in the liver and macrophages. LAL couples intracellular lipid metabolism to functions of the immune cells by providing FC and FFAs that are used for cell proliferation and acquisition of effector functions. Restoring LAL activity improves metabolic parameters in LALD and ameliorates the immunoinflammatory response. Human recombinant LAL ERT might represent a therapeutic approach to correct impaired immune cell functions. [ABSTRACT FROM AUTHOR]