L16 Immunometabolism Flashcards
what is metabolism? + the basics
Metabolism: * Chemical reactions in living organisms for:
- Food conversion into energy (catabolism) and components (anabolism)
- Waste elimination
basics
Glucose → Pyruvate (glycolysis: catabolic- transferring glucose generates atp and anabolic- most intermediates generate other molecules. Pentosephosphates generates nucleotides e.g: rna.)
* It is anaerobic process (hypoxia)
* Not very efficient (low ATP)
* Generates NADH (anabolism)
* Provides biosynthetic intermediates:
G6P – Nucleotides (PPP)
3PG – Aminoacids (serine)
Pyruvate – TCA
Citric Acid Cycle (TCA)
* In the mitochondria
* Under normoxia
* High NADH - Transfer e- to ETC - OXPHOS
Oxidative Phosphorylation (OXPHOS): the most efficient way to gen atp
* Electron transport chain
* High ATP
Fatty Acid Oxidation (FAO): depends on lipids to be imported by the cell.
* High ATP
* Acetyl-CoA, NADH – TCA - OXPHOS
Glutaminolysis
* Alternative input TCA - OXPHOS
* Citrate - FAS
Pentose Phosphate Pathway (PPP): anabolic.
* Diversion from glycolysis into nucleotide
– nucleic acid biosynthesis
* High NADPH – FAS and redox
Fatty Acid Synthesis (FAS)
Biosynthesis of FA, TAG, PL
(tag- triacylglycerides)
Cholesterol biosynthesis pathway (cbp)
Cholesterol (and oxysterols)
* Isoprenylation mediators
* N-glycosylation
Anabolism regulators?
If cells are in good environment with glucose, oxygen and growth factors (gf firstly activate pI3K and then mTOR. mTOR is activated and promotes Hif1-a (alpha) and c-myc: 2 transcription factors. C-myc- tf that tells cells to synthesise proteins and therefore anabolism to gen elements and divide and grow. Synthesise membranes, dna and proteins. biosynthesis of proteins and lipids drives cell cycle and cell cycle progression.
when does catabolism>anabolism?
Ratio between amp and atp changes (amp greater than atp). Amp kinase blocks mTOR and hif1-alpha as cell does not have enough glucose to synthesise things. Happens in tumour microenvironment. Ampk activation is a problem but is a natural way for cell to control atp prod. energy conservation programme: glucose to OXPHOS. blockade of protein and lipid biosynthesis.
immune response terminology?
Naive : Quiescent (do not divide)
Effector : Dividing-
differentiating
Memory: Resting-
Differentiated
Metabolic reprogramming occurs essentially moving the cells through these stages i guess.
Naive t cells: few mitochondria, big nucleus. Have excess glucose as they live in the blood where there is lots. Import glucose, perform some oxphos but generally metabolically inactive. Not good at performing glycolysis.
Naive t cells have huge pool of mrna that synthesise effector molecules and enzymes.
Effector t cells: cell bigger, more mitochondria.
importance of metabolic reprogramming?
Immune response happens in diff parts of body so essential to divide and differentiate quickly. If metabolic reprogramming does not happen then immune response does not happen. Happens in all immune cells:
Blood
Tissue
metabolic reprogramming provides ATP (energy) (catabolism), synthesise cellular components (anabolism), REGULATE IMMUNE FUNCTION.
Immune cells do not use glucose like other cells within the body. Immune cells use glycolysis when activated.
How do immune cells use metabolism?
Proliferation, differentiation= increased protein synthesis, lipid demand, atp demand.
Not dependent on glucose but dependent on antigen. Antigen needed for this.
Warburg effect: Normally, cells generate energy (ATP) by using oxidative phosphorylation (OXPHOS), a highly efficient process in the mitochondria that requires oxygen.
The Warburg Effect is when cells switch to generating energy through glycolysis, even when oxygen is present. Glycolysis is less efficient but much faster, and it creates byproducts that are useful for cell growth and division.
Why is this important for immune cells? When T cells or other immune cells are activated (e.g., by encountering an antigen), they need rapid energy and materials for proliferation and effector functions. So, they switch to glycolysis to meet these demands.
Metabolism of effector cells relies on glycolysis and glutaminolysis as they do not have much mitochondria for oxphos. Effector cells use anabolic side e.g: for nucleotides that synthesise dna for dividing. Effector cells do not have much mitochondria so in 24h can synthesise mitochondrial mass. When activated not enough mitochondria to use oxphos effectively.
The carbons from glucose (glutamine) are used for:
* Fast activation – rapid ATP generation (catabolism)
* Generation of metabolites to support proliferation
and differentiation (anabolism)
Effector to memory cells: Lipids -> FAO ->
OXPHOS
Glutaminolysis
Glycolisis
CBP
Mesh of mitochondria in memory cells is more complex. Have the mitochondrial power needed to perform oxphos effectively. Already selected for antigen, have metabolic programme needed to perform it very quickly. Perform little glycolysis.
Immunometabolism: Moonlight in T cells
Glucose metabolism elements…. as transcriptional and post-transcriptional regulators
of the adaptive immune response.
In a resting cd4 or cd8 t cel,GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) iis bound to interferon gamma mRNA. Stop from being translated into protein as GAPDH blocks so ribosome cannot bind. No translation. In naive t cell so cannot produce cytokines.
Tcr signals, activated, cell performs glycolysis. GAPDH is called to glycolysis and transforms glucose to pyruvate. So mrna of interferon gamma is free and ribosome can be activated.
Chatgpt:
The “moonlighting function” in this context refers to GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) having a dual role:
Primary (metabolic) role: In glycolysis, GAPDH converts glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, a critical step in energy production.
Moonlighting (non-metabolic) role: In resting T cells, GAPDH binds to interferon-gamma (IFN-γ) mRNA and blocks its translation by preventing the ribosome from attaching to the mRNA.
immune cells in tumour?
Immune cells, such as CD8+ T cells, can become exhausted in the tumour microenvironment due to metabolic stress.
Normal Glucose Environment:
When the T cell receptor (TCR) is engaged, glycolysis is activated to meet the energy demands of the cell.
A byproduct of glycolysis, phosphoenolpyruvate (PEP), plays an important role in supporting the immune response.
PEP can modulate signaling pathways (such as NFAT, nuclear factor of activated T cells) critical for T cell function and antitumour activity.
Tumour Microenvironment:
In tumours, glucose availability is often restricted because tumour cells consume glucose rapidly (a phenomenon known as the Warburg Effect in cancer).
Without sufficient glucose, T cells cannot sustain glycolysis, leading to reduced PEP production.
Low PEP levels impair NFAT activation, which is essential for the transcription of genes involved in the immune response.
As a result, CD8+ T cells are less effective at mounting an antitumour response.
immunometabolism: macrophages (M1 and M2)
Macrophages and Their Types
M1 Macrophages (“Pro-inflammatory”):
M1 macrophages differentiate in response to bacterial infections or inflammatory signals (like LPS, a bacterial component, IFN-Y and Bacterial PAMPS).
They are responsible for secreting pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and producing reactive oxygen species (ROS).
These macrophages are associated with pro-inflammatory responses and are key in fighting infections.
Their metabolic state is reprogrammed to support this function.
be aware pro inf and stuff isn’t mentioned
M2 Macrophages (“Anti-inflammatory”):
M2 macrophages are associated with immune regulation, tissue repair, and resolving inflammation.
They help in wound healing by promoting granulation tissue formation and repairing damaged tissue.
Metabolic Reprogramming in M1 Macrophages
Metabolic Shift:
When macrophages receive a signal (like LPS binding to TLR4), they undergo a process called metabolic reprogramming to support their pro-inflammatory functions.
.
M1 metabolism?
Activation of mTOR and HIF-1α:
LPS activates mTOR (mechanistic target of rapamycin) and HIF-1α (hypoxia-inducible factor 1-alpha).
HIF-1α is typically activated under low oxygen, but in macrophages, its activation can occur independently of oxygen levels due to LPS signaling.
Glycolysis Dominance (Warburg Effect):
Like effector T cells, M1 macrophages rely heavily on glycolysis (breaking down glucose for energy) instead of the full TCA cycle.
This shift (similar to the Warburg Effect in cancer cells) allows for rapid energy production and supports inflammatory functions.
Disruption of the TCA Cycle
When M1 macrophages are activated:
The TCA cycle (Krebs cycle) is broken into two parts.
The cycle is interrupted between citrate and aconitate, leading to the accumulation of citrate and succinate.
Key Metabolic Effects:
Citrate Accumulation:
Citrate is used for the biosynthesis of molecules needed for inflammation (e.g., fatty acids, prostaglandins).
It is also converted to itaconate, a molecule with antibacterial properties. This is an M1-specific defense mechanism.
Succinate Accumulation:
Succinate stabilizes and activates HIF-1α, which enhances the production of IL-1β, a key pro-inflammatory cytokine. Citrate facilitates biosynthesis. Citrate transforms in itaconate. Antibacterial. M1 specific mechanism.
M2 metabolism?
Cytokine Signals: IL-4 and IL-13
These anti-inflammatory cytokines activate M2 macrophages.
IL-4 and IL-13 bind to their receptors on macrophages, triggering intracellular signaling pathways.
STAT6 Activation:
The binding of IL-4 or IL-13 activates the STAT6 (Signal Transducer and Activator of Transcription 6) pathway.
STAT6 drives the transcription of genes that support anti-inflammatory responses and tissue repair.
PPAR and RXR Activation:
PPAR (Peroxisome Proliferator-Activated Receptor) and RXR (Retinoid X Receptor) are nuclear receptors that modulate lipid metabolism and gene expression.
These receptors work together to drive metabolic changes necessary for M2 macrophage functions, including fatty acid metabolism.
M2 macrophages rely on oxidative metabolism rather than glycolysis, in contrast to M1 macrophages. This includes:
- Triglyceride (TG) Breakdown to Fatty Acids:
M2 macrophages metabolize triglycerides into fatty acids as their main energy source.
Fatty Acid Oxidation (FAO):
- The fatty acids undergo β-oxidation in mitochondria, generating energy in a slow but sustained manner.
This metabolic pathway supports their prolonged anti-inflammatory and tissue-repair functions.
Intact TCA Cycle and Oxidative Phosphorylation (OXPHOS): - Unlike M1 macrophages, M2 macrophages have a fully functional TCA cycle (Krebs cycle) and oxidative phosphorylation (OXPHOS).
These processes provide efficient energy production and reduce oxidative stress, aligning with their roles in anti-inflammatory responses.
Functional Outcomes
Prolonged Responses:
M2 macrophages are metabolically optimized for long-term activity, supporting sustained anti-inflammatory and tissue repair functions.
Granulation Tissue Repair:
The metabolic pathways drive the production of molecules needed for wound healing and granulation tissue formation, like collagen and extracellular matrix proteins.
Anti-Inflammatory Gene Expression:
M2 macrophages upregulate genes involved in immune regulation, reducing inflammation and resolving tissue damage.
M2 feed on lipids like memory t cells. Tca not broken. Perform oxphos. Have lots of mitochondria. Make sure m2 are long lived
Tregs immunometabolism?
live on lipids like memory t cells. But diff mechanisms and functions.
main metabolic pathways: FAO, high CBP = tolerance (immune response)
cellular immunometabolism summary?
Naive T cell: glucose-OXPHOS immune response- quiescence
EFFECTOR T, M1: glycolysis, glutoaminolysis, FAS, low CBP. immune response: pro-inf cytokine prod
memory T, M2: glutoaminolysis, lipid, FAOS, OXPHOS. quick response upon ag encounter, anti-inf cytokine prod
and treg already said
