Myeloid Cell Metabolism Research Articles

Abstract We052: Angiotensin-converting enzyme (ACE): A new role to regulate β-oxidation in monocytic cells

The metabolic failure of macrophages to adequately process lipid, and the deleterious effects of ingested lipid on macrophage behavior, is central to the etiology of atherosclerosis. As angiotensin-converting enzyme (ACE) has major effects on myeloid cell metabolism, we examined the role of macrophage ACE in a mouse model of atherosclerosis. Animals with increased macrophage ACE expression (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and higher levels of effector molecules downstream of PPARα. These macrophages have increased basal and maximal oxygen consumption compared to WT macrophages. When exposed to lipid in vitro, ACE 10/10 macrophages ingest more fatty acid than WT and have increased efferocytosis. ACE 10/10 macrophages metabolize via β oxidation far more fatty acid than WT cells as determined using 13C isotope tracing. In part by increasing PPARα, ACE boosts myeloid metabolic function under pathophysiologic lipid stress, addressing a key myeloid failure in atherosclerosis.

EP2 inhibition restores myeloid metabolism and reverses cognitive decline.

Nonsteroidal anti-inflammatory drugs alleviate pain and inflammation by inhibiting the cyclooxygenase pathway. This pathway has various downstream effects, some of which are beneficial. Prostaglandin E2 is a key downstream product in the cyclooxygenase pathway that modulates inflammation. Acorrelation between aging and increased expression of the prostaglandin E2 receptor, EP2, has been associated with inflammatory processes, cognitive aging, angiogenesis, and tumorigenesis. Therefore, inhibition of EP2 could lead to therapeutic effects and be more selective than inhibiting cyclooxygenase-2. Studies suggest that inhibition of EP2 restores age-associated spatial memory deficits and synaptic proteins and impairs tumorigenesis. The data indicate that EP2 signaling is important in myeloid cell metabolism and support its candidacy as a therapeutic target.

Sytemic and Cellular Metabolic Phenotype of Infection and Immune Response to Listeria monocytogenes

Abstract It is generally accepted that immune response and pathogen clearance are metabolically demanding. Additionally, shifts in cellular metabolism are known to occur during immune responses. However, we lack a grasp of how the numerous components of protective immunity contribute to the metabolic demand of illness. Previous studies using model antigens or purified PAMPs have been unable to represent the dynamics of live pathogen infection and immune response. Therefore, we sought to measure the systemic and cellular metabolism of infection and immune response to a well-characterized bacterial pathogen, Listeria monocytogenes. Mice infected with Listeria were monitored over the course of 12 days in multi-parameter metabolic cages. The metabolic phenotype data collected included body weight, activity, sleep, respiratory exchange rate, and energy expenditure. In a parallel study, mice infected with Listeria were utilized to measure bacterial burden, Listeria-specific T cell response, and cellular metabolism of the immune system. We found the early stages of infection (day 1–5), corresponding to the kinetics of the innate immune response, had the greatest metabolic impact on the organism as indicated by weight loss, reduced activity, increased sleep, and decreased energy expenditure. At later timepoints, corresponding to the timing of the adaptive response, there was little evidence of metabolic impact over uninfected controls. We also observed changes in myeloid cell metabolism over the course of the infection. Overall, our results indicate that the innate immune response is more metabolically demanding, compared to the adaptive immune response, linking “sickness behavior” to the timing of the innate immune response.

The metabolic regulation in immune cells and pathogenesis of systemic lupus erythematosus ∼toward new therapeutic applications∼.

The importance of cellular metabolism has long been known as Warburg effect; cancer cells are characterized by mitochondrial defect that shifts towards aerobic glycolysis. Recently, many reports have revealed that immune metabolism is a key factor for controlling immune cell proliferation and differentiation. Resting lymphocytes generate energy through oxidative phosphorylation and fatty acid oxidation, whereas activated lymphocytes rapidly shift to glycolysis. Especially in T cells, more precise mechanism of regulating metabolism have been clarified on differentiation from naïve T cells to effector T cells. Similar studies have also been carried out to characterize B cell and myeloid cell metabolism. Metabolic regulation is considered to be particularly important in autoimmune diseases. Metabolic changes in these diseases might not only reflect the chronic activated immune-status but also associated with their pathogenesis. Here, we review what is known on the altered metabolism in systemic lupus erythematosus (SLE), mainly focusing on T cells and B cells, and how they contribute to SLE pathogenesis. We also discuss how immune metabolic defects can become targets of future SLE therapy.

Calcium-binding myeloid protein (P8,14) is phosphorylated in fMet-Leu-Phe-stimulated neutrophils

In this report, we show that the p14 subunit of calcium-binding myeloid protein complex (p8,14) is phosphorylated in human neutrophils stimulated with either fMet-Leu-Phe, phorbol myristate acetate, or a calcium ionophore. Trifluoperazine, a calmodulin antagonist, caused hyperphosphorylation of p14 in intact resting neutrophils. Preincubation of resting cells with 10-20 nM calyculin A, a potent protein phosphatase inhibitor, also caused enhanced labeling of p14, which was further progressively increased on stimulation with fMLP. Thus, the phosphorylation level of p14 in resting as well as in stimulated neutrophils appears to be controlled by an active protein phosphatase. The phosphorylation of p14 by a chemoattractant and by a phorbol ester is a novel finding supporting the current belief that p8,14 myeloid protein may play an important role in the metabolism of myeloid cells.