Abstract
Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine, into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow–derived macrophages cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag–quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated that addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing the pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation, to aid in the phenotypic transition toward alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation toward proresolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h after LPS stimulation that included succinate dehydrogenase complex, pyruvate kinase, and sedoheptulokinase. Se-dependent modulation of these pathways predisposed bone marrow–derived macrophages to preferentially increase oxidative phosphorylation to efficiently regulate inflammation and its timely resolution. The use of macrophages lacking selenoproteins indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of succinate dehydrogenase complex with dimethylmalonate affected the proresolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and proresolution.
Highlights
Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine, via tRNA[Ser]Sec dependent decoding of the UGA codon in 24 murine (25 in humans) selenoproteins [1, 2]
It is evident that changes in intracellular metabolic pathways, such as glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, impact cellular functions in immune cells [27, 28]
LPSactivated macrophages inhibit expression of several enzymes of the TCA cycle, including succinate dehydrogenase (Sdh) complex [14] leading to accumulation of succinate and increased activation of hypoxia inducible factor-1α (Hif-1α) and IL-1β culminating in high glycolytic rates to favor M1 polarization [30]
Summary
Activation of macrophages and effect of Se supplementation on global proteome Based on the previously reported effects of Se and selenoproteins in favoring M2-like phenotype switching in macrophages [21], we comprehensively characterized the effects of. Expression of Sdha in Trsp KO BMDMs was decreased at time points 0, 4, and 8 h after LPS but increased at 20 h in the presence of 250nM selenite treatment, indicating an opposite effect that corroborated the modulation of cellular succinate levels (Fig. 5, B and C). DMM treatment led to a slight increase in total F4/80+ macrophages in response to Zymosan A stimulation (Fig. 8B), while decreasing the M2like macrophages (F4/80+ CD206+) in the peritoneal lavage fluid (Fig. 8C) compared to the PBS control These studies further corroborate in vitro observations and suggest that a Se-dependent increase in succinate oxidation is key to timely resolution of inflammation
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