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

From my understanding of Robert Phairs technical description the innate immune system can affect CAD via interferon-alpha/JAK pathway and that pathway has positive feedback. What you are describing seems to be positive feedback of type 1 interefron's in Macrophages. Does this make sense?

Some scRNA-seq ME/CFS (link) and Long Covid studies have identified monocytes as having significant genetic differences vs health controls, more so than other immune cells, which is why what is happening to Macrophages might be of interest in both diseases.

 

To the connection to ME/CFS I need to do a bit more reading on that. But from brief look that I could do, I like the itaconate hypothesis a lot. It is fitting and can explain the symptoms. But it needs experimental verification. I can see a connection through it being a self sustaining mechanism, where in presence of itaconate, you get more interferon which can boost itaconate production in surrounding cells.

Irg1 is triggered also with stimuli that do not induce IFNb in macrophages. One can imagine a scenario, ewhere itaconate is induced first and interferon activation happens later, resulting in a stronger response.

First I need to see some things verified by myself. For example:
1. how are CoA levels changing in presence/absence of itaconate.
2. What are the actual levels of itaconyl-CoA in the glial cells uon activation.
3. Can we devise a mouse model of ME/CFS that would help us understand and verify available hypothesis.

I believe we have tools and exertise to answer these questions. But it will take some time.

 

The way CAD (I'm more used to IRG1) activation is described is not exhaustive. It is one of the pathways that can induce it. The reason I'm saying "Type I IFN" is that it is group of interferons alpha and beta that both signal through IFNAR receptor.

Yes there is definitely a positive feedback loop fot IFN production. Without it, there is almost no IFN. I can write more on that if you are interested.

 

Hi @paulendat, welcome to the forum! It's great to have more people with an immunometabolism background interested in ME/CFS!

I’m very interested in these findings, since I (as a graduate student with ME/CFS) am looking into possible mechanisms by which type I interferon production could be triggered at higher levels than normal after physical exertion in ME/CFS (as an attempt to explain post-exertional malaise, a hallmark symptom of the illness).

I'm just starting to learn about cellular metabolism in-depth, so I’d like to make sure I’m understanding your point correctly here. Are you saying that natural itaconate likely only inhibits interferon production via upregulating ROS generation, which in turn activates the Nrf2 pathway?

If so, in a situation where itaconate is upregulated but ROS production is temporarily inhibited, would you expect that to result in higher levels of type I interferons?

I ask because I'm hypothesizing a (potentially global) weak impairment of the malate-aspartate shuttle in ME/CFS. I am not sure what point would be impaired, but SDH or GOT2 inhibition are options that I am looking into at the moment.

My thought is that if the rate of malate shuttling is impaired, situations with higher ATP demand could not be met by oxidative phosphorylation, as eventually the store of mitochondrial NADH would be depleted faster than it can be replenished. I may be incorrect, but I suspect that a state of reduced mitochondrial NADH would inhibit mtROS generation temporarily since I have read that it is dependent on the proton gradient.

I know that in regular exercise, we see pretty immediate TNF/IL-6/etc. responses from macrophages, but this normally resolves over time without further consequence in healthy subjects. (To that point, I suspect that the same malate-aspartate shuttle mechanism would prevent cortisol production from being ramped up in response). I am not sure if type I interferons would also be upregulated in that situation, but if they are, reliance on ROS for suppression might explain a delayed and prolonged malaise after exertion in ME/CFS.

Would be very curious to hear your thoughts!

 

@jnmaciuch

I will answer point by point

Are you saying that natural itaconate likely only inhibits interferon production via upregulating ROS generation, which in turn activates the Nrf2 pathway?

No, ROS induced by itacoonate boost IFNb production. Due to it not being strong enough to induce strong NRF2 response.

The induction of NRF2 pathway happens for example in LPS activation where we see a difference between cells producing itaconate (WT) and those lacking itaconate (Irg1-KO). Irg1-KO shows weaker NRF2 activation. This can be explained as itaconate being an activator of NRF2. Or that ROS elevated due to inhibition of PRDX5 by itaconate boost NRF2. However, we need to prove this to be true.

 

@paulendat you can use the «multiquote» feature to make it easier to respond to other comments.

There’s a button at the bottom of each comment to add the entire comment, or you can highlight individual sections to only add those. When you have added something to your multiquote list, an «Insert Quotes» button will appear below the text editor box.

An added benefit of the multiquote is that it notifies the people you quote so you don’t have to remember to tag them.

 

Thank you that's perfectly clear. I thought I must be getting mixed up somehow!

Brain fog and not being a scientist make these conversations tricky to follow sometimes!

 

Thanks for the clarification, I had missed your earlier explanation that interferon I production was also dependent on ROS and misinterpreted your response to Hutan. I’ve had a chance to read the whole paper now, congrats on the great publication!

In that case, it might actually make perfect sense with the delayed (usually 24-48 hrs) aspect of PEM—interferon production (triggered by itaconate) would be limited by any temporary situation which inhibited by ROS production, correct?

 

Thank you, I appreciate it.

This is very important thing to answer. The delay can be explained by the fact that expression of Irg1 doesn't really start until 4h post activation for example. Real meaningful itaconate levels happen even later. I would think that the delay would simply be the time needed for itaconate effects to accumulate enough to manifest.

But this is pure speculation on my part.
That is something worth working on.

 

That's very interesting--funnily enough, I noticed quite a change in the time frame of PEM once I started taking a stimulant for ME/CFS. Previously it would take 1-2 days for those symptoms to manifest. On a stimulant, it would take 3-4 hours after starting activity.

Obviously that's just one person's experience, but I've been digging to see if there might be an explanation related to glucose uptake or something else that would be affected in tissue by dextroamphetamine.

Thanks for taking the time to explain! I am quite limited in what I can study in the lab myself, so it is very encouraging for me that someone else is interested in answering the same questions. I look forward to your future work!

 

Hi @paulendat

Happy to see someone from my country who is interested in ME/CFS field. I lead ME/CFS facebook group where is around 1000 slovak and czech patients. I also have a good connection to LC groups in our country. If you find interesting to somehow cooperate with us don´t hesitate to contact me.
Good luck with your research

 

Hi tuha,
This is wonderful. Can you share who's the long covid group?

We are planning things on the fly at the moment. But this could be an amazing resource in the near future if people would be willing to participate in a study. 1000 people is a great number.

 

Sorry for that. Open access is crazy expensive.

My paper is also available on researchgate with the fulltext.

https://www.researchgate.net/public...e_responses_via_inhibition_of_peroxiredoxin_5

Let me know if it works for you.

 

Also a summary of this research in Nature Metabolism's "News & Views" section:

https://doi.org/10.1038/s42255-025-01274-1

 

Paywalled unfortunately for me.

 

There are 2 facebook groups which I know:
ME/CFS Slovensko - myalgická encefalomyelitída / chronický únavový syndróm (950 members)
https://www.facebook.com/groups/661691970549488

Long covid a postcovidový syndrom - ČESKO A SLOVENSKO (4 400 members)
https://www.facebook.com/groups/longcovidczsvk

In these groups you can find patients for ME/CFS or LC studies. What could be problem in Slovakia, that there is no ME/CFS or LC doctor, so there can be a lot of patients who got ME/CFS or LC diagnosis but they dont have it.

 

Perhaps we here could help by suggesting what might be a good screening questionnaire, if @paulendat is interested. And maybe one specifically about PEM. (I'm not offering, I don't know!)