An evolutionary perspective on immunometabolism

Wang, Andrew; Luan, Harding H.; Medzhitov, Ruslan

doi:10.1126/science.aar3932

Cited by 295 publications

(286 citation statements)

References 105 publications

(108 reference statements)

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“…[43][44][45] Reduced ribosomal activities may also be the consequences of reduced oxidative phosphorylation and ATP synthesis because protein synthesis via ribosomal activity is among the most energy-consuming processes. 46 Different from myeloid cells, T cell activation and polarization also require increased oxidative phosphorylation to obtain a vast energy demand 47,48 and in our study, the impaired oxidative phosphorylation and ribosomal activity in LPS pigs support well the trend of suppressed Th1 polarization. The increased immune suppression and reduced metabolic activities in LPS vs CON pigs are also similar to that observed in preterm vs term monocytes, 5 and in septic conditions.…”

Section: Discussionsupporting

confidence: 81%

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

et al. 2019

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Chorioamnionitis (CA, fetal membrane inflammation) predisposes to preterm birth and is associated with increased neonatal infection risk, but the separate effects of prematurity, CA, and postnatal adaptations on this risk are unclear. Using pigs as models for infants, we examined the systemic immune‐metabolic status in cesarean‐delivered preterm pigs, with and without CA induced by intra‐amniotic (IA) LPS exposure. At birth, cord blood of preterm pigs showed neutropenia and low expressions of innate and adaptive immune genes, relative to term pigs. IA LPS induced CA and fetal systemic innate immune activation via complement and neutrophil‐related pathways. These were mainly modulated via cellular regulations rather than granulopoiesis, as validated by the in vitro LPS stimulation of cord blood. After birth, IA LPS‐exposed preterm pigs did not follow normal immune‐metabolic ontogenies found in fetuses or newborns without prenatal insults, but showed consistently high levels of Treg, impaired Th1 polarization, and reduced expressions of multiple genes related to cellular oxidative phosphorylation and ribosomal activities. In conclusion, our results provide cellular and molecular evidence for CA‐induced distinct neonatal immune‐metabolic status with increased disease tolerance strategy, suggesting mechanisms for the clinical observation of elevated sepsis risks in immune‐compromised preterm infants born with CA.

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Section: Discussionsupporting

confidence: 81%

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

et al. 2019

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“…While SCFA reduce innate immune activation of primary tissue in the absence of acute T cell inflammation, such as during early stages of UC, they might exert opposing effects in progressed acute UC with negative consequences for the hepatobiliary system. Activated, highly proliferative T cells largely require glucose for a robust response while resting immune cells switch fuel usage from glucose to fatty acids and ketones in support of tissue-protective pathways (65). However, SCFA and increased production of ketone bodies measured during interaction studies, further increased T cell effector function.…”

Section: Resultsmentioning

confidence: 99%

“…Figures S1-S9 Table S1 References (64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)…”

Section: Supplementary Materialsmentioning

confidence: 99%

Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids

Trapečar

Communal

Velazquez

et al. 2019

Preprint

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Association between the microbiome, IBD and liver diseases are known, yet cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver and circulating Treg/Th17 cells, we modeled progression of ulcerative colitis (UC) ex vivo. We show that microbiome-derived short-chain fatty acids (SCFA) may either improve or worsen disease severity, depending on the activation state of CD4 T cells. Employing multiomics, we found SCFA reduced innate activation of the UC gut and increased hepatic metabolism. However, during acute T cell-mediated inflammation, SCFA exacerbate CD4 T cell effector function leading to gut barrier disruption and liver damage. These paradoxical findings underscore the emerging utility of human physiomimetic technology to study causality and temporal facets of gut-liver axis related diseases where animal models leave ambiguity.

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“…Finding that glutamine reduced pyolysin-induced cell death if given before, but not after pyolysin challenge also supports a role for glutamine in protecting cells, rather than damage repair. The beneficial role of glutamine in tissue cytoprotection complements the role glutamine plays in immune cell metabolism and supporting inflammatory responses to pathogens [9, 36].…”

Section: Discussionmentioning

confidence: 99%

Glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins from pathogenic bacteria

Turner

Owens

Sheldon

2019

Preprint

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Pathogenic bacteria often damage tissues by secreting toxins that form pores in cell membranes, and the most common pore-forming toxins are cholesterol-dependent cytolysins. During bacterial infections, glutamine becomes a conditionally essential amino acid, and glutamine is an important nutrient for immune cells. However, the role of glutamine in protecting tissue cells against pore-forming toxins is unclear. Here we tested the hypothesis that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins. Stromal and epithelial cells were sensitive to damage by cholesterol-dependent cytolysins, pyolysin and streptolysin O, as determined by leakage of potassium and lactate dehydrogenase from cells, and reduced cell viability. However, glutamine helped protect cells against cholesterol-dependent cytolysins because glutamine deprivation increased the leakage of lactate dehydrogenase and reduced the viability of cells challenged with cytolysins. Without glutamine, stromal cells challenged with pyolysin leaked lactate dehydrogenase (control vs. pyolysin, 2.6 ± 0.6 vs. 34.4 ± 4.5 AU, n = 12), which was more than three-fold the leakage from cells supplied with 2 mM glutamine (control vs. pyolysin, 2.2 ± 0.3 vs. 9.4 ± 1.0 AU). The cytoprotective effect of glutamine was not dependent on glutaminolysis, replenishing the Krebs cycle via succinate, changes in cellular cholesterol, or regulators of cell metabolism (AMPK and mTOR). In conclusion, although the mechanism remains elusive, we found that glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins from pathogenic bacteria.

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An evolutionary perspective on immunometabolism

Cited by 295 publications

References 105 publications

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids

Glutamine supports the protection of tissue cells against the damage caused by cholesterol-dependent cytolysins from pathogenic bacteria

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