Immunometabolism Flashcards
What is immunometabolism?
20 years ago TNFalpha administration was shown to lead to hyperglycemia
Later experiments with obese rodents foundthat neutralisation of TNF-alpha improved insulin resistance with TNF-alpha deficient mice having improved insulin sensitivity during diet induced diabetes
This established a connection between the immune system and metabolism leading to the formation of a new field
How is there a common modular architecture between immunity and metabolism?
They both have sensors which transduce stimuli into downstream mediators that activate effector responses to eliminate stimulis and therefore lead to a return to homoestasis
How do immune cells mediate inflammation in adipose tissue?
In the lean state the environment is anti-inflammatory and insulin sensitive however in the obese state immune cells are recruited and the recruited monocytes are polarized to highly proinflammatory M1 state where they lead to insulin resistance along with cytokines/chemokines that stimulate inflammation in other tissues in an endocrine manner
What are the cytokine changes observed in the lean and obese adipose tissue?
In the obese state proinflammatory cytoikes TNF-alpah, IFN gamma IgG2c antibodies and the Th1 response is amplified while in the lean state proresolving cytokines such as IL-4, IL-10, IL-13 and the Th2 response is amplified
What is the connection between infection, immunity and insulin resistance?
Bacterial infection activates innate immune cells to release pro-inflammatory cytokines, this can result in insulin resistance in metabolic tissues as well as increased gluconeogenesis in the liver, decresed glucose disposal in the muscle and increased breakdown of glycogen
This elevated glucose can then fuel immune cell activation
Insulin resistance in adipose tissues causes increased breakdown of lipids and decreased lipogenesis
Elevated FFAs can support immune cell metabolic demands
What are the signalling pathways that contribute to insulin resistance?
Stimulation of proinflammatory signalling pathways negatively regulate insulin signalling leading to insulin resistance
TNF-alpha can stimulate serine kinases that leads to serine phosphorylation of insulin receptor substrate 1
Saturated fatty acids can signal through TLRs to regulate proinflammatory gene expression
Inflammasome activation also contributes to the pro-inflammatory signalling
Omega-3 fatty acids and IL-10 anti-inflammatory signalling decrease insulin resistance
What signals can lead to M1 polarization?
Hif1alpha
AP1 (activator protein 1)
What signals can lead to M2 polairzation?
PPAR-gamma (peroxisome proliferator-activated receptor gamma)
KLF4 (Kruppel-like factor 4)
IRF4 (Interferon regulatory factor 4)
What occurs in M2 macrophage-adipocyte signalling in the lean state?
It inhibits the macrophage from responding to further pro-inflammatory signals
What occurs in M1 macrophage-adipocyte signalling in the obese state?
Proinflammatory signalling perpetuated by cross talk between M1 macrophage and inflamed adipocyte
A feed forward loop
M1 cells release CD5-like antigen which is taken up by the adipocyte via CD36 mediated endocytosis which promotes the breakdown of lipids into short chain fatty acids which perpetuate M1 activation and adipocyte pro-inflammatory phenotype
What are the altered metabolic modes of immune cells?
Oxphos-oxidation of nutrients in the mitochondria to produce energy (TCA cycle and electron transport chain)
Or TCA cycle, metabolic pathway to generate ATP via the oxidation of acetate from glucose, fats or amino acids
What is the Warburg effect?
This is when ATP production and cellular survival is dependent on glycolysis and there is no OXPHOS even in the presence of O2
The pentose phosphate pathway is active and proved NADPH which is needed for nox-dependent bactericidal activity
What is the function of aerobic glycolysis and OXPHOS in immune cells?
Activated T cells use aerobic glycolysis and OXPHOS with degradation of glutamine being able to help replenish the TCA cycle intermediates
What is the role of mitochondrial ROS in immune cells?
A by product of OXPHOS, NADH and succinate from the TCA cycle feed into the respiratory chain to generate ATP
Electrons leak from the respiratory chain to form superoxide makingthe ithe primary source of cellual ROS
How is mROS regulated?
Immunoreceptors, PI3K, Hypoxia, Cytokines and Calcium all augment mROS production
While Anti-oxidants, Mitophagy and a decrease in mitochondrial membrane potential will all inhibit mROS formation
