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Lecture 5. Immunometabolism and the immune system (AM_470656)
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The role of metabolism in the immune response.
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Molecular Cell Biology and ImmunologyLecture 5. Immunometabolism
INDEX
1. What are the metabolic needs of macrophages? ........................................................................................................................................ 1
2. Metabolic enzymes regulate immune responses ......................................................................................................................................... 2
3. Metabolites regulate immune responses .................................................................................................................................................... 2
3.1. Itaconate ............................................................................................................................................................................................ 3
3.1.1. Mechanisms of action .......................................................................................................................................................................... 3
4. techniques .................................................................................................................................................................................................. 4
, Immunometabolism → How certain pathways can lead to an immune response. We look at the metabolism of the immune cells, the professor
focuses on macrophages and he will focus on that, but other cells also are shaped by their metabolism.
Some years ago, immunology was more centered in the immunology of diseases, but metabolism is very important. They understand how the
metabolism functions or does not, and how it relate to disease and its progression. → In the lab they look at the pathways.
The functions of macrophages: they can kill tumor cells, they phagocytose, they present information, but a lot of inflammatory diseases are also
driven by them. they also have a resolving effect on inflammation, they intervene in healing, and they dampen the immune response. After the
infection they resolve inflammation and make sure the IR is dampened and does not damage. → The functions that make macrophages very
good in wound healing also make them very good in promoting tumor growth. Depending on the environment you want an activation state, you
can do that by targeting the metabolism.
Different functions require different metabolic pathways. → You can compare it to running, where running = IR and it is not the same running a
marathon and a sprint. The homeostasis macrophages are more like marathon runners, they have to be there for a longer time, and they have
to remain there. Host defense against pathogen do not have time to waste, they have to be metabolically very different.
Review. A guide to immunometabolism for immunologists
This is a field that is rapidly evolving and pretty recent (10 years). Some of the things they describe are a bit more black and white. Take home
messages (exam):
- Different macrophage functions require different metabolic activities.
- Metabolic enzymes regulate immune responses.
- Metabolites regulate immune responses.
- TCA cycle is not a cycle anymore, it is like chaos and sometimes it helps the inflammatory response.
EXAM. Explain the metabolic pathways that support the inflammatory and anti-inflammatory macrophages and T cells. Give examples of how
metabolic enzymes and metabolites can regulate the immune response. Also, imagine what kind of metabolic pathway we would like to
inhibit/promote to make the macrophages go to a more antitumoral response.
M1=killers; M2=anti-inflammatory
1. WHAT ARE THE METABOLIC NEEDS OF MACROPHAGES?
M1 macrophages are:
- Glycolysis: they are highly glycolytic, this makes for a high ATP generation.
- TCA cycle is very directed to generate citrate.
- High pentose phosphate pathway activity: it can generate ROS to kill pathogens.
- Fatty acid synthesis: anabolic.
o In T cells it is used to make new membranes to proliferate.
o In macrophages it is important to enable the release of cytokines.
- Amino acid metabolism
- In general, they have an anabolic state to synthesis a lot of different molecules.
M2 macrophages are important in helminth infections. They have:
- Normal TCA cycle: for oxidative phosphorylation (OX-Phos) that is a
normal way of functioning.
- Fatty acid oxidation, they also burn glucose.
- Amino acid metabolism
- They are long-lived and they generate a lot of ATP.
Amino acid metabolism is very different in M1 and M2.
- Nitric oxide
- Arginase activity. Arginine metabolism was one of the 1st ways to
discriminate between M1 and M2 in the 1990s.
o Arginine can be converted by an inducible synthase,
induced by a product from cytokines. After this, they make
NO and this leads to the killing response in cells (killing
bacteria or tumor cells).
1
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