Leucine Reconstitutes Phagocytosis-Induced Cell Death in E. coli-Infected Neonatal Monocytes-Effects on Energy Metabolism and mTOR Signaling.

Published on Apr 20, 2021in International Journal of Molecular Sciences5.924
· DOI :10.3390/IJMS22084271
Stephan Dreschers7
Estimated H-index: 7
Kim Ohl16
Estimated H-index: 16
+ 2 AuthorsThorsten W. Orlikowsky16
Estimated H-index: 16
MΦ differentiate from circulating monocytes (Mo). The reduced ability of neonatal Mo to undergo apoptosis after E. coli infection (phagocytosis-induced cell death (PICD)) could contribute to sustained inflammatory processes. The objective of our study was to investigate whether immune metabolism in Mo can be modified to gain access to pro-apoptotic signaling. To this end, we supplemented Mo from neonates and from adults with the branched amino acid leucine. In neonatal Mo, we observed increased energy production via oxidative phosphorylation (Oxphos) after E. coli infection via Seahorse assay. Leucine did not change phagocytic properties. In neonatal Mo, we detected temporal activation of the AKT and mTOR pathways, accompanied with subsequent activation of downstream targets S6 Kinase (S6K) and S6. FACS analyses showed that once mTOR activation was terminated, the level of anti-apoptotic BCL-2 family proteins (BCL-2; BCL-XL) decreased. Release of cytochrome C and cleavage of caspase-3 indicated involvement of the intrinsic apoptotic pathway. Concomitantly, the PICD of neonatal Mo was initiated, as detected by hypodiploid DNA. This process was sensitive to rapamycin and metformin, suggesting a functional link between AKT, mTOR and the control of intrinsic apoptotic signaling. These features were unique to neonatal Mo and could not be observed in adult Mo. Supplementation with leucine therefore could be beneficial to reduce sustained inflammation in septic neonates.
Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis ("first inflammatory hit"). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia ("se...
#1Sung Min Son (University of Cambridge)H-Index: 4
#2So Jung Park (University of Cambridge)H-Index: 20
Last. David C. Rubinsztein (University of Cambridge)H-Index: 144
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Macroautophagy (“autophagy”) is the main lysosomal catabolic process that becomes activated under nutrient-depleted conditions, like amino acid (AA) starvation. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-conserved negative regulator of autophagy. While leucine (Leu) is a critical mTORC1 regulator under AA-starved conditions, how Leu regulates autophagy is poorly understood. Here, we describe that in most cell types, including neurons, Leu negatively regulates autophagosome ...
#1Federico Carbone (UniGe: University of Genoa)H-Index: 28
#2Fabrizio Montecucco (UniGe: University of Genoa)H-Index: 60
Last. Amirhossein Sahebkar (MUMS: Mashhad University of Medical Sciences)H-Index: 111
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ABSTRACTIntroduction: Mortality due to sepsis is still prevalent, peaking at extreme ages of life including infancy. Despite many efforts, the peculiarity of the infant immune system has limited fu...
The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signallin...
#1Danay Cibrian (UAM: Autonomous University of Madrid)H-Index: 14
#2Raquel Castillo-González (UAM: Autonomous University of Madrid)H-Index: 4
Last. Francisco Sánchez-Madrid (UAM: Autonomous University of Madrid)H-Index: 122
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Abstract Background Psoriasis is a frequent inflammatory skin disease, mainly mediated by IL-23, IL-1β, and IL-17 cytokines. Although psoriasis is a hyper-proliferative skin disorder, the possible role of amino acid transporters has remained unexplored. Objective To investigate the role of the essential amino acid transporter LAT1 (SLC7A5) in psoriasis. Methods LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of Keratin 5, CD4 and RORγt. We produced models of skin ...
#1Shaonan Liang (THU: Tsinghua University)H-Index: 4
#2Liangliang Ji (THU: Tsinghua University)H-Index: 3
Last. Xiaoyu Hu (THU: Tsinghua University)H-Index: 34
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Abstract Immune responses are often accompanied by radical changes of cellular metabolism of immune cells. On the other hand, an ever increasing number of metabolic pathways and products have been found to possess immune regulatory functions. The field of immunometabolism that investigates the interplay between metabolism and immunity has developed rapidly during the past decade. In this chapter, we attempt to summarize the recent progresses by scientists in China on metabolic regulation of inna...
#1Christopher Platen (Boston Children's Hospital)H-Index: 4
#2Stephan Dreschers (Boston Children's Hospital)H-Index: 7
Last. Thorsten W. Orlikowsky (Boston Children's Hospital)H-Index: 16
view all 7 authors...
Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphireg...
#1Dubek Kazyken (UM: University of Michigan)H-Index: 3
#2Brian Magnuson (UM: University of Michigan)H-Index: 17
Last. Diane C. Fingar (UM: University of Michigan)H-Index: 22
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AMP-activated protein kinase (AMPK) senses energetic stress and, in turn, promotes catabolic and suppresses anabolic metabolism coordinately to restore energy balance. We found that a diverse array of AMPK activators increased mTOR complex 2 (mTORC2) signaling in an AMPK-dependent manner in cultured cells. Activation of AMPK with the type 2 diabetes drug metformin (GlucoPhage) also increased mTORC2 signaling in liver in vivo and in primary hepatocytes in an AMPK-dependent manner. AMPK-mediated a...
#1Stephan Dreschers (RWTH Aachen University)H-Index: 2
#2Kim Ohl (RWTH Aachen University)H-Index: 16
Last. Klaus Tenbrock (RWTH Aachen University)H-Index: 35
view all 11 authors...
Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy met...
#1Bernard Kan (UBC: University of British Columbia)H-Index: 8
#2Christina Michalski (UBC: University of British Columbia)H-Index: 5
Last. Pascal M. Lavoie (UBC: University of British Columbia)H-Index: 29
view all 15 authors...
Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of...
Cited By1
#2Diyuan Zhou (Soochow University (Suzhou))H-Index: 5
Last. Xinyu Shao (Nanjing Medical University)H-Index: 2
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