Selenium-dependent metabolic reprogramming during inflammation and resolution

Abstract

Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine (Sec), 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 (BMDMs) 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 addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing PPP, TCA cycle, and OXPHOS, to aid in the phenotypic transition towards alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation towards pro-resolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h post LPS stimulation that included succinate dehydrogenase complex (Sdh), pyruvate kinase (Pkm), and sedoheptulosekinase (Shpk). Se-dependent modulation of these pathways predisposed BMDMs to preferentially increase OXPHOS to efficiently regulate inflammation and its timely resolution. Use of macrophages lacking selenoproteins, indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of Sdh with dimethylmalonate affected the pro-resolving 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.

Orally administered Odoribacter laneus improves glucose control and inflammatory profile in obese mice by depleting circulating succinate

“…Interestingly, plasma succinate was associated with several KEGG functions directly related to succinate metabolism, such as malonate decarboxylase (EC:4.1.1.87), which inhibits succinate dehydrogenase, and isocitrate lyase (EC:4.1.3.1), and others without a direct link that might be the consequence of indirect interactions. Notably, several genes involved in selenate metabolism such as selenate reductase (EC:1.97.1.9) were found to be significantly linked to succinate and a recent publication has described selenium as a mediator of metabolic reprograming that facilitates anti-inflammation and pro-resolution [75]. Our analysis also revealed an upregulation of genes related to the phosphoenolpyruvate (PEP) node, being the most relevant phosphonopyruvate decarboxylase, which carboxylates PEP to oxalacetate and is the primary fermentative route for succinate [76] Remarkably, our study on Krebs cycle-related genes in association with fecal succinate revealed several genes significantly upregulated, with DLST (EC:2.3.1.61) and succinyl-coA synthetase (EC:6.2.1.5) being the most significant.…”

Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation

“…In this study, we found remarkable reduction of Fah expression coupled with lower levels of fumarate suggesting an altered tyrosine catabolism in Selenow −/− BMDMs. Decreased levels of fumarate is also reminiscent of a disrupted TCA cycle as previously reported in selenium deficient BMDMs, where no selenoproteins, including SELENOW, were expressed [ 13 , 36 ]. Inhibition of succinate dehydrogenase (SDH-A) with dimethylmalonate in mice maintained on selenium replete diets increased the time for resolution in a model of peritonitis indicating that decreased fumarate is a sign of disrupted metabolism and resolution [ 13 ].…”

“…Decreased levels of fumarate is also reminiscent of a disrupted TCA cycle as previously reported in selenium deficient BMDMs, where no selenoproteins, including SELENOW, were expressed [ 13 , 36 ]. Inhibition of succinate dehydrogenase (SDH-A) with dimethylmalonate in mice maintained on selenium replete diets increased the time for resolution in a model of peritonitis indicating that decreased fumarate is a sign of disrupted metabolism and resolution [ 13 ]. Together, these results imply that SELENOW may play a role in arginine and tyrosine metabolism.…”

“…Reduced levels of circulating selenoprotein P (SELENOP) and total selenium in sepsis patients [ 25 ] could limit the selenium availability during acute inflammation to impact cellular response to inflammation [reviewed in 5]. We previously demonstrated that SELENOW, a highly selenium responsive protein, was one of the most abundantly expressed selenoproteins in inflamed BMDMs, implicating its plausible association in the inflammatory pathways [ 13 ]. Although the steady-state levels of selenoprotein genes and proteins have been reported earlier [ 12 ], we examined their temporal changes during the progression of inflammation, which remains largely unknown.…”

“…The inherent plasticity of macrophages is associated with metabolic adaptations that sustain their polarization towards a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, which is regulated by diverse factors, including cytokines, bioactive lipid mediators, as well as efferocytosis of apoptotic neutrophils. To this end, previous studies demonstrated that Selenow mRNA [ 12 ] and protein [ 13 ] were highly expressed in bone marrow-derived macrophages (BMDMs) in response to exogenous selenium supply.…”