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

@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?

 

Here is a little backstory of our discovery. It is public and short. Should be accessible to everyone.


https://communities.springernature.com/posts/itaconate-and-prdx5-how-did-we-get-here

 

Thank you, I'll do my best to get to this. Currently working on many fronts. plus i'm getting ready to speak to leaders in ME/CFS research. Sorry for not reacting readily.

 

Thank you for that, it is really interesting. It's always heartening to see people stubbornly persisting at something and questioning received wisdom.

 

Thank you for sharing!

 

That's great, and very exciting for us! Thank you for getting involved.

 

Max Artyomov (priciple investigator in this story) has a talk in Harvard seminar series. It just came to my attention that it will be streamed on zoom tomorrow. It will be scientifically heavy talk. But some of you may find it interesting.

https://immunologyphd.hms.harvard.e...-university-school-medicine-st-louis?occ_id=0

 

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.

 

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".

 

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?

 

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.

 

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.

 

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]

 

So the shunt can be imposed on other cells by itaconite diffusing from cell to cell?
And the signal to the microglia could be PAMP or DAMP? Could it also be an endogenous cytokine or even neurotransmitter signal?

 

@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.

 

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.

 

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.

 

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).