| Popis: |
Macrophages are innate immune cells and are involved in the body’s first line of cellular defence. During an immune response, pro-inflammatory and reparative homeostatic macrophage activation states outbalance each other to prevent excessive damage. A disruption in this balance can result in inflammatory disorders, like atherosclerosis, obesity, and multiple sclerosis (MS) where inflammatory activation prevails. In response to activation stimuli, macrophages rewire their metabolism to support their function. Targeting these cellular processes can be a potential therapeutic target to steer cells toward a reparative direction. Therefore, this thesis aimed to study the interplay of macrophage metabolism and macrophage functioning to explore therapeutic potential. Metabolic alterations in macrophage activation states can be measured with a multitude of assays, but finding the best-suited method may be challenging. In chapter 2 we combined several immunometabolic methods into a toolbox and applied these to stimulated macrophages. A suitable combination of these methods can reveal specific metabolic rewiring of macrophages and may be used as a toolbox for measuring immune cell metabolism for researchers new to the field. Alterations in whole-body metabolism can affect macrophage activation states, as high circulating cholesterol levels (hypercholesterolemia) are a major risk factor for atherosclerosis, a disease mainly driven by macrophages. In chapter 3, we showed that diet-induced hypercholesterolemia induces rewiring of the pentose phosphate pathway in lipid-rich foamy macrophages, halting the inflammatory activation of these cells. This connects altered systemic metabolism to changes in macrophage metabolism and subsequent altered cellular function. Next to altered diet, genetic defects may also affect systemic and cellular metabolism. Patients with genetic defects in long-chain fatty acid oxidation (lcFAOd) present with the breakdown of muscle tissue (rhabdomyolysis) and the accumulation of acylcarnitines in blood and tissues, two mechanisms that can be related to inflammation. In chapter 4 we studied the metabolism and function of these patients’ immune cells. Monocytes and macrophages did not show affected cellular phenotype, metabolism, or function, indicating that long-chain FAO may not be a valuable target for inflammatory disorders in general. Inflammatory overactivation of macrophages and other immune cells prevails in inflammatory diseases like atherosclerosis, sepsis, obesity, and MS. In chapters 5, 6 and 7, we set out to elucidate the therapeutic potential of targeting ATP citrate lyase (Acly) in macrophages in atherosclerosis and other inflammatory disorders. Acly is an enzyme that converts citrate into acetyl-CoA for lipid metabolism. In chapter 5, we showed that although a deficiency of Acly increased inflammatory activation and reduced IL-4-induced activation of macrophages, plaques presented to be more stable, and thereby lowered the risk for myocardial infarction and stroke. As targeting Acly induced hyperinflammatory activation of macrophages (chapter 5), we wanted to rule out induction of hyperinflammation in other inflammatory diseases or comorbidities. In chapter 6 we showed that deletion of macrophage-Acly does not potentiate worsening of obesity-induced inflammation or sepsis-like inflammation. These results indicate that targeting macrophage-Acly is beneficial in atherosclerosis, but not in other studied inflammatory disorders. Hypercholesterolemia is often treated with cholesterol-lowering drugs and some patients receive a drug called bempedoic acid, an Acly-inhibitor. Bempedoic acid is specifically activated by liver cells, and hereby solely inhibits Acly in the liver. In chapter 7, we combined our findings from chapters 5 and 6 and discussed them in the context of recent findings on atherosclerosis treatment with bempedoic acid and Acly in macrophages. Based on our results, it would be valuable to further evaluate targeting Acly in both macrophages and liver cells in atherosclerosis. Generally, this thesis shows that macrophage metabolism (the powerhouse) can be rewired upon systemic metabolic alterations and that it presents opportunities for therapeutic treatment of inflammatory disorders. |
