Itaconate modulates immune responses via inhibition of peroxiredoxin 5, 2025, Tomas Paulenda et al

Jonathan Edwards said:
Hi, Tom. This is a somewhat 'philosophical' post but one that tries to get at how we structure our disease models at a high (overview) level. My background is in rheumatoid arthritis where our identification of switches from negative to positive feedback loops helped me identify the B cell depleting agent rituximab as a useful therapy.

ME/CFS is another acquired disease that seems to switch on and often persist, although, like RA, sometimes it switches off. I think there must be a similar point where a negative feedback loop gets diverted to a positive loop which gets stuck. Robert Phair suggested this might occur at the itaconate level in an 'itaconite trap'. I find that intuitively implausible but I am not exactly sure why.

I think my argument would be that we need a plausible acquired cellular regulatory change that persists. For 'acquired' mitochondrial myopathies I understand that to be cells with abnormal mDNA competing out other cells. For RA the shift seems to be the generation of new recombinations of Ig genes that encode 'subversive' antibodies. For cancer it is a malignant clone. For BSE it is prion polymerisation. For psychosis it may be synaptic rearrangement that leads to cycles of abnormal cognition.

Basically, I see three ways that an acquired cellular change can persist and cause system-wide disease. One is a change in DNA - cancer, and also RA. Another is a change in nerve connections - psychosis maybe. The third is something I think people miss out on and I would call supramolecular pattern propagation. This would include amyloid and BSE. It might be the basis of Alzheimer's. The error is perpetuated by a pattern of repeating molecules that self-propagates, a bit like the 'flyers' in Conway's Life Game. It is conceivable that this can occur in musculoskeletal tissues with things like TGF beta binding - what I call the 'Writing on the Wall' model.

And my problem with an itaconite trap is that I don't see how, in practice, you get propagation of a switch from a negative loop to a positive one within the metabolic machinery of a cell. Where have the railway points been switched over? For sure, if the cell has been infected with a retrovirus the DNA can do the switch, but where would there be switches within the metabolic pathways that could persists and also propagate from cell to cell. So I look for ways signalling between cells could be switched. And I guess that although I understood the interest of thinks like ITIMs and STAT kinases I always focused on the outside signals.

But, as has already come up in the discussion, there is of course powerful information in knowing the intracellular signals both because they might be blocked by drugs and because their time courses and cross-interactions may be crucial to the clinical expression of the story. I like the idea that we might be able to pin down the delay of PEM by working out the time course of mediating steps. PEM may be too variable to make that easy but there is no doubt that we are dealing with a signalling mechanism that can take many hours.

There is also the interesting question, raised by Hutan here, as to whether metabolic shifts cause symptoms such as difficulty using muscles, directly, or through invoking neural or other indirect signals.

What I am increasingly confident of is that somewhere in all this interaction between immune and nerve signals and internal cell metabolic shifts lies the answer to ME/CFS. I personally doubt that anyone 'runs out of ATP'. I think more likely some cells tell other cells to go on strike and refuse to use their ATP. But the evidence remains very hard to interpret. Hopefully we will have some genetic clues soon, so now is the time to really focus in on this problem.
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@paulendat Just wanted to bring your attention back to this post by Jonathan.. do you have any comment on the points he raises on the itaconate trap mechanism/ theory?
 
Jonathan Edwards said:
Hi, Tom. This is a somewhat 'philosophical' post but one that tries to get at how we structure our disease models at a high (overview) level. My background is in rheumatoid arthritis where our identification of switches from negative to positive feedback loops helped me identify the B cell depleting agent rituximab as a useful therapy.

ME/CFS is another acquired disease that seems to switch on and often persist, although, like RA, sometimes it switches off. I think there must be a similar point where a negative feedback loop gets diverted to a positive loop which gets stuck. Robert Phair suggested this might occur at the itaconate level in an 'itaconite trap'. I find that intuitively implausible but I am not exactly sure why.

I think my argument would be that we need a plausible acquired cellular regulatory change that persists. For 'acquired' mitochondrial myopathies I understand that to be cells with abnormal mDNA competing out other cells. For RA the shift seems to be the generation of new recombinations of Ig genes that encode 'subversive' antibodies. For cancer it is a malignant clone. For BSE it is prion polymerisation. For psychosis it may be synaptic rearrangement that leads to cycles of abnormal cognition.

Basically, I see three ways that an acquired cellular change can persist and cause system-wide disease. One is a change in DNA - cancer, and also RA. Another is a change in nerve connections - psychosis maybe. The third is something I think people miss out on and I would call supramolecular pattern propagation. This would include amyloid and BSE. It might be the basis of Alzheimer's. The error is perpetuated by a pattern of repeating molecules that self-propagates, a bit like the 'flyers' in Conway's Life Game. It is conceivable that this can occur in musculoskeletal tissues with things like TGF beta binding - what I call the 'Writing on the Wall' model.

And my problem with an itaconite trap is that I don't see how, in practice, you get propagation of a switch from a negative loop to a positive one within the metabolic machinery of a cell. Where have the railway points been switched over? For sure, if the cell has been infected with a retrovirus the DNA can do the switch, but where would there be switches within the metabolic pathways that could persists and also propagate from cell to cell. So I look for ways signalling between cells could be switched. And I guess that although I understood the interest of thinks like ITIMs and STAT kinases I always focused on the outside signals.

But, as has already come up in the discussion, there is of course powerful information in knowing the intracellular signals both because they might be blocked by drugs and because their time courses and cross-interactions may be crucial to the clinical expression of the story. I like the idea that we might be able to pin down the delay of PEM by working out the time course of mediating steps. PEM may be too variable to make that easy but there is no doubt that we are dealing with a signalling mechanism that can take many hours.

There is also the interesting question, raised by Hutan here, as to whether metabolic shifts cause symptoms such as difficulty using muscles, directly, or through invoking neural or other indirect signals.

What I am increasingly confident of is that somewhere in all this interaction between immune and nerve signals and internal cell metabolic shifts lies the answer to ME/CFS. I personally doubt that anyone 'runs out of ATP'. I think more likely some cells tell other cells to go on strike and refuse to use their ATP. But the evidence remains very hard to interpret. Hopefully we will have some genetic clues soon, so now is the time to really focus in on this problem.
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Hi Jonathan,

This is indeed very deep and requires some thought.

I agree that cellular basis of ME/CFS is very much needed to be understood.

Obvious go to would be neurons. I would expect changes there. But those are likely consequences of some other change. The hypothesis of Rob and Ron seems plausible to me if you consider depletion of neurotrasmiters. Here lies a direct answer. However, we still don't know what exactly is happening and changing. The problem is that one may need to probe serum and blood in time when the episode starts to see what is the acute change and trigger compared to normal state. And from what I understand so far, this is very tricky in this type of disease.

In my opinion, we need to be able to control the timing.

The beauty of itaconate is that it is restricted to immune cells. This narrows the search down significantly.

I think we really need a disease model for ME/CFS. I have ideas, what can be done to create such model in mouse. Once we have that, possibilities to investigate are huge and searching for a responsible cell type will become easier.

That is my outlook at the moment. Still fairly limited, I admit. I would like to talk to you more in near future about this if you won't mind. And we can see where we find common ground and identify potential problems and solutions.
 
paulendat said:
The hypothesis of Rob and Ron seems plausible to me if you consider depletion of neurotrasmiters.
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To clarify this for those that are not aware, from what I remember from having watched the videos a year or two ago, the itaconate shunt hypothesis predicts a switch from glucose to amino acid use in the brain. Neurotransmitters are one source of amino acids (Glutamate/Glutamine), and so that could be a possible reason for "depletion of neurotransmitters".
 
paulendat said:
I think we really need a disease model for ME/CFS. I have ideas, what can be done to create such model in mouse. Once we have that, possibilities to investigate are huge and searching for a responsible cell type will become easier.
Click to expand...

I am interested in hearing more about how we would create such a model. We have a hard enough time determining PEM in humans and we don't have the luxury of asking the mice what they are experiencing. Is there a way to reliably give mice ME/CFS?
 
paulendat said:
That is my outlook at the moment. Still fairly limited, I admit. I would like to talk to you more in near future about this if you won't mind. And we can see where we find common ground and identify potential problems and solutions.
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Fair enough, Tom. I am happy to do a Zoom or Teams if you like, although I am too old to know how to set those up myself. I am in the process of co-writing a review on this overview level of analysis and a specific suggestion for an immune mechanism. It involves an interferon. I have the potential advantage that I no longer have to write grants or papers or worry about protecting my own ideas, because I have been there, done that. So I am happy to discuss anything and everything I know about, but respect ownership of other people's ideas.
 
I have been listening to Robert Phair's first video on the taconite shunt idea.

One question I have is which cells make use of the shunt. I think Tom noted that taconite generation was restricted to immune cells. Pahir talks about viral target cells (which can be epithelial or neural or whatever) using it to shut down TCA cycle activity. I am unclear how that works if taconite is only used by immune cells?

Phair seems to imply that taconite is switched on in brain cells by an 'innate immune signal' but doesn't seem to say what that would be.

I am going to look at his second video which sounds more relevant to the question I originally posed.
 
Jonathan Edwards said:
I have been listening to Robert Phair's first video on the taconite shunt idea.

One question I have is which cells make use of the shunt. I think Tom noted that taconite generation was restricted to immune cells. Pahir talks about viral target cells (which can be epithelial or neural or whatever) using it to shut down TCA cycle activity. I am unclear how that works if taconite is only used by immune cells?

Phair seems to imply that taconite is switched on in brain cells by an 'innate immune signal' but doesn't seem to say what that would be.

I am going to look at his second video which sounds more relevant to the question I originally posed.
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One type of glial cells are microglia. These are essentially brain macrophages. They are innate immune cells that can get activated by myriad of signals and are known to produce itaconate. As we show in the paper the signal can be Damage associated patterns or Pathogen associated patterns. They all induce itaconate production irrespective of Type I interferon production.
 
Jonathan Edwards said:
I have been listening to Robert Phair's first video on the taconite shunt idea.

One question I have is which cells make use of the shunt. I think Tom noted that taconite generation was restricted to immune cells. Pahir talks about viral target cells (which can be epithelial or neural or whatever) using it to shut down TCA cycle activity. I am unclear how that works if taconite is only used by immune cells?

Phair seems to imply that taconite is switched on in brain cells by an 'innate immune signal' but doesn't seem to say what that would be.

I am going to look at his second video which sounds more relevant to the question I originally posed.
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https://www.sciencedirect.com/science/article/pii/S2772892724000798

This review mentions that itaconate import has been observed in both T cells and hepatocytes. I think it is not out of the question that the itaconate importer is expressed on other non-immune cell types—I will look into this question further.

I believe that the effect of itaconate on succinate dehydrogenase is not unique to immune cells either, and SDH is present in most (if not all?) cell types. If itaconate gets imported into local tissue cells, it would impair TCA cycle and oxidative phosphorylation directly, causing those cells to shift to other methods of ATP production

[edit: including the metabolic sensing neurons mentioned in another thread, potentially]
 
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@Jonathan Edwards @jnmaciuch
Itaconate uptake has been shown for number of cell types, including T cells.

But, one thing has to be considered and this is where I'm not yes convinced these effects can be driven by itaconate transfer to other cells.

Itaconate is not a very potent inhibitor of SDH. Hence, quite large concentrations are required for it's action. These are concentrations that are reached in activated macrophages. But, after export/import to another cell, they don't reach necessary levels in my opinion. I'm planning experiments to verify this. I haven't seen for example an experiment where supernatant (media) from activated WT/Irg1-KO (unable to produce itaconate) macrophages would induce SDH inhibition in any cell of choice.
 
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I still haven't heard any satisfactory explanation of PEM with itaconate shunt or whatever-trap. So, I dug up and re-read Cort's writing on it, and still haven't found one. Robert Phair's response on it seems to confuse PEM with fatigue, so that wasn't a good sign. At least he seems to be saying what I've been saying: the trial of the drug predicted by the hypothesis is the ultimate test.

I wouldn't put too much hope on a theory unless it can explain PEM in a straightforward manner. And I would define PEM as "the worsening of symptoms after physical or mental exertion, even after minimal activity, with symptoms typically appearing 12 to 48 hours later and lasting for days or weeks", not long-standing fatigue.
 
paulendat said:
Itaconate uptake has been shown for number of cell types, including T cells.

But, one thing has to be considered and this is where I'm not yes convinced these effects can be driven by itaconate transfer to other cells.

Itaconate is not a very potent inhibitor of SDH.
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Thanks, I am beginning to get a picture.
The other thing that seems counterintuitive is that the macrophage should be inhibiting its own metabolism in response to danger signals. I would expect it to want to have as much metabolic resources as possible. The cell that does not want to encourage virus to grow in it is usually another cell.

I have managed to view both the Phair videos now. I am not sure I see a convincing reasoning for an interferon alpha self-driving positive feedback loop getting stuck. This gets back to the 'disease memory' worry for a chronic acquired illness.

I can otherwise see quite a bit of overlap with what I have been mulling over, in terms of cells being inhibited from full functioning by an immune signal, but I am still tending to think we need an adaptive immune shift involved.
 
paulendat said:
@Jonathan Edwards @jnmaciuch
Itaconate uptake has been shown for number of cell types, including T cells.

But, one thing has to be considered and this is where I'm not yes convinced these effects can be driven by itaconate transfer to other cells.

Itaconate is not a very potent inhibitor of SDH. Hence, quite large concentrations are required for it's action. These are concentrations that are reached in activated macrophages. But, after export/import to another cell, they don't reach necessary levels in my opinion. I'm planning experiments to verify this. I haven't seen for example an experiment where supernatant (media) from activated WT/Irg1-KO (unable to produce itaconate) macrophages would induce SDH inhibition in any cell of choice.
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Thanks for the clarification--I'd be really interested in your verification. If it's true that it is not a potent enough SDH inhibitor, I'd be interested to look at other potentially stronger inhibitors of SDH (or other enzymes acting on TCA cycle metabolites).
 
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