NLRP3-Mediated Glutaminolysis Regulates Microglia in Alzheimer's Disease

McManus, Róisín M.; Komes, Max P; Griep, Angelika; Santarelli, Francesco; Schwartz, Stephanie; Perea, Juan Ramón; Khalil, Michelle‐Amirah; Lauterbach, Mario A.; Heinemann, Lea; Schlüter, Titus; Alcazar, Juan F. Rodriguez; Schmidt, Susanne F.; Spitzer, Jasper; Noori, Peri; Maillo, Alberto; Tegnér, Jesper; Hiller, Karsten; Latz, Eicke; Heneka, Michael T.

doi:10.2139/ssrn.4178538

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…In the absence of glucose, glutaminolysis can step in to sustain microglial functional responses elicited by a lesion in brain slices (Bernier et al, 2020). Furthermore, glutamine metabolism in microglia is regulated by NLRP3, such that loss of NLRP3 increases glutamine/ glutamate-related metabolism, which results in enhanced mitochondrial and metabolic activity (McManus et al, 2022).…”

Section: G Lutaminolys Is Fuel S Anti -Infl Ammatory Re S P Ons E Smentioning

confidence: 99%

“…Notably, a ketogenic diet (i.e., high‐fat, low‐carbohydrate content diet, 3.1:1 lipid‐to‐carbohydrate and protein ratio, respectively) administered to spinal cord injury rats transforms microglia from pro‐ to anti‐inflammatory phenotypes following injury, resulting in improved long‐term functional recovery (Kong et al, 2021). The low‐carbohydrate content in ketogenic diets could lead to reduced glycolytic flux, and increased mitochondrial respiration; pathways known to promote anti‐inflammatory microglial phenotypic transitions (Cheng et al, 2021; Liu et al, 2017; McManus et al, 2022; York et al, 2021). Ketone oxidation therefore occurs concomitantly with other metabolic pathways known to be associated with immune response.…”

Section: Ketone Bodies Inhibit Microglial Activationmentioning

confidence: 99%

“…These diverse and energy‐demanding functions require the metabolism of glucose, amino acids, lipids, and ketone bodies, and their intermediate metabolites serve as biosynthetic precursors for reactions that regulate transitions between inflammatory states (Ferreira et al, 2022; Hirschberger et al, 2021; Sumbria et al, 2021; Zhou et al, 2022). The rates at which substrates are used and which pathways are employed for their catabolism are linked to microglial phenotypic states (Button et al, 2014; Guillot‐Sestier et al, 2021; McManus et al, 2022). Immunometabolism constitutes the changes in metabolic pathways in cells during immune activation (O'Neill et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…low-carbohydrate content in ketogenic diets could lead to reduced glycolytic flux, and increased mitochondrial respiration; pathways known to promote anti-inflammatory microglial phenotypic transitions(Cheng et al, 2021;Liu et al, 2017;McManus et al, 2022; York F I G U R E 5 Cholesterol inhibits lipid oxidation and stimulates glycolysis and lipid de novo biosynthesis in microglia. Despite not contributing to energy production, cholesterol promotes broad metabolic adaptations in microglia.…”

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confidence: 99%

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Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain‐infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro‐ and anti‐inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro‐inflammatory activation is associated with decreased mitochondrial respiration, whereas anti‐inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post‐traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non‐resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post‐traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.image

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Section: G Lutaminolys Is Fuel S Anti -Infl Ammatory Re S P Ons E Smentioning

confidence: 99%

Section: Ketone Bodies Inhibit Microglial Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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“…Nonetheless, the increase of aerobic glycolisis in lieu of oxidative phosphorylation does not reduce the importance of mitochondrial respiration to regulate and energetically support proinflammatory immune response mechanisms. In macrophages for instance, it has been shown that mitochondrial electron transport system is required for NLRP3 inflammasome activation and that this is fueled by glutamine oxidation (22,23). In addition, the role of mitochondrial metabolism in immune response surpasses energy production, because the accumulation of intermediaries of the tricarboxylic acid cycle (TCA) cycle, such as succinate and itaconate, may also serve as signaling triggers that drive pro-inflammatory IL-1β and anti-inflammatory IL-10 production, respectively (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Short-Term Inflammatory Biomarker Profiles Are Associated With Deficient Mitochondrial Bioenergetics in Lymphocytes of Septic Shock Patients—a Prospective Cohort Study

Nedel¹,

Strogulski

Rodolphi

et al. 2022

Shock

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Introduction: A biomarker strategy based on the quantification of an immune profile could provide a clinical understanding of the inflammatory state in patients with sepsis and its potential implications for the bioenergetic state of lymphocytes, whose metabolism is associated with altered outcomes in sepsis. The objective of this study is to investigate the association between mitochondrial respiratory states and inflammatory biomarkers in patients with septic shock. Methods: This prospective cohort study included patients with septic shock. Routine, complex I, complex II respiration, and biochemical coupling efficiency were measured to evaluate mitochondrial activity. We measured IL-1ß, IL-6, IL-10, total lymphocyte count, and C-reactive protein levels on days 1 and 3 of septic shock management as well as mitochondrial variables. The variability of these measurements was evaluated using delta counts (days 3–1 counts). Results: Sixty-four patients were included in this analysis. There was a negative correlation between complex II respiration and IL-1ß (Spearman ρ, −0.275; P = 0.028). Biochemical coupling efficiency at day 1 was negative correlated with IL-6: Spearman ρ, −0.247; P = 0.05. Delta complex II respiration was negatively correlated with delta IL-6 (Spearman ρ, −0.261; P = 0.042). Delta complex I respiration was negatively correlated with delta IL-6 (Spearman ρ, −0.346; P = 0.006), and delta routine respiration was also negatively correlated with both delta IL-10 (Spearman ρ, −0.257; P = 0.046) and delta IL-6 (Spearman ρ, −0.32; P = 0.012). Conclusions: The metabolic change observed in mitochondrial complex I and complex II of lymphocytes is associated with a decrease in IL-6 levels, which can signal a decrease in global inflammatory activity.

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NLRP3 inflammasome signalling in Alzheimer's disease

McManus,

Latz

2024

Neuropharmacology

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NLRP3-Mediated Glutaminolysis Regulates Microglia in Alzheimer's Disease

Cited by 4 publications

References 29 publications

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Short-Term Inflammatory Biomarker Profiles Are Associated With Deficient Mitochondrial Bioenergetics in Lymphocytes of Septic Shock Patients—a Prospective Cohort Study

NLRP3 inflammasome signalling in Alzheimer's disease

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