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

[Jonathan Edwards]

I've read this entire thread and I still don't understand how any of this is relevant to the physiology/symptoms of ME/CFS? Maybe @jnmaciuch can enlighten me?

Have you watched Robert's two videos, because they are very clear. He suggests that per is due to ammonia accumulation in brain. The general theory would also predict reduced metabolic capacity for various tissues (if we think that is what we are looking for).

 

[Snow Leopard]

Have you watched Robert's two videos, because they are very clear. He suggests that per is due to ammonia accumulation in brain. The general theory would also predict reduced metabolic capacity for various tissues (if we think that is what we are looking for).

We'd have additional signs if there was ammonia accumulation in the brain and that evidence is lacking.

Ammonia easily crosses the blood-brain barrier so there would be higher levels in circulation as well.
https://my.clevelandclinic.org/health/diseases/24065-hyperammonemia

 

[Jonathan Edwards]

We'd have additional signs if there was ammonia accumulation in the brain and that evidence is lacking.

I agree, although we may not have a comparable clinical situation of pure cerebral ammonia toxicity in the context of reduced metabolic reserve.

 

[jnmaciuch]

I've read this entire thread and I still don't understand how any of this is relevant to the physiology/symptoms of ME/CFS? Maybe @jnmaciuch can enlighten me?

Agreed with Jonathan, though I think there are still additional missing pieces/contradictions with literature (which, to be clear, is to be expected from any theory so I am not disregarding it out of hand on those reasons). If this theory is correct, you would assume it leads to accumulation of the metabolites which trigger the metabosensing afferents you have brought up mediating central fatigue. As already mentioned, though, I think the link to PEM is a big missing piece here. Like you, I am not convinced brain ammonia levels are sufficient to explain for several reasons (personal opinion, take it or leave it).

I am also particularly thinking of Cara Tomas’s group and their muscle metabolism work, which showed comparable functioning between healthy and ME/CFS via galactose-only oxidative phosphorylation and fatty acid metabolism, both of which would be reliant on acetyl-CoA making it through the TCA cycle. I suppose if it’s a “weak” itaconate shunt it might be compensated by glutamine to some extent [or simply increased throughput through either pathway to counteract lack of efficiency. FAO also does produce some NADH independent of Acetyl-CoA output].

And like I said earlier, I have doubts as to whether a solely parenchymal response would be able to upregulate IRG1 to a sufficient extent. If the initial parenchymal response led to tissue resident macrophage activation during exertion, then I could see it being sufficiently propagated through those macrophages, and the local metabolic depression would be explained by itaconate inhibition of SDH alone or perhaps by those macrophages simply outcompeting parenchymal cells for glucose.

But there are doubts as to whether even high levels of itaconate from macrophages could do this in other cells, and we don’t see other signs of macrophage activation that you would expect from Nf-kB upregulation.

 

[Trish]

We have moved some posts about experiences with stimulants and malic acid to this members only thread.

 

[jnmaciuch]

It is, but from my prior work in macrophages I have never seen it being stimulated by IFNAR or IFNGR activation alone. In macrophages, this is induced via co-stimulation of interferons and LPS, or another TLR activator [edit: leading to both Nf-kB and STAT TF binding to facilitate ACOD1 transcription]. You would likely need to induce a strong Nf-kB response alongside IFN, which would be confounded by the normal regulators of Nf-kB in non-immune cells. Hence my skepticism as to whether parenchymal cells can upregulate ACOD1 enough to cause this metabolic dysfunction. Of course, there might be new information in the future that challenges this.

Just following up on this thought, since I’ve spent the last several months working on multiple datasets and reviewing literature on interferon signaling for one of my PhD projects. I can pretty much confirm that ACOD1/IRG1 is not an ISG that gets expressed in any of the many types of tissue cells I have looked at. The only cell types that express it (outside of some rare cases like cancerous cells) are myeloids, and that is only under conditions that trigger multiple signaling cascades (i.e. TLR stimulation), not from interferon alone.

Interferon alone is also not enough to trigger more interferon—you need NFkB and ATF activation as well (plus some other TFs like CREB, I believe, for strong induction). All those cascades get triggered simultaneously in canonical interferon stimulation via cytosolic viral DNA/RNA sensing or PAMP detection in immune cells, but they are not stimulated by interferon signaling alone. In any infection dataset, for example, you will have only a small subset of actively infected cells producing interferon, and the remaining bystander cells express cell-type specific ISGs not including interferon.

 

[Amw66]

This is fascinating:



I'd never considered that we should focus on early-onset cases. Ron Davis focused on the severely ill to get the biggest ME/CFS 'signal'. I wonder if early onset and severity are correlated and if not, why not.

Early onset , pre puberty , may give a clearer picture of any predisposition prior to puberty kicking in ?

 

[Amw66]

I favour the double tap. Childhood here saw chickenpox disturb something
Glandular fever in teenage years was the second "tap" smack bang when bodies are chemical soups..
It seemed like a viral tag team.
Do viral (and bacterial ) strains work together , if so which ones are known / prevalent and how do they fool the immune system

As we have varying onsets , the switches on the rails may differ , but are there common junctions?

There are also suppositions
The IDO hypothesis was founded where the loss / difference in genetic expression was not thought to matter as the other gene would cover it
Other pathways no doubt have such suppositions , would these also potentially factor in
Glutathione for example ?

ETA I have not read whole thread yet so this may be redundant

 

[V.R.T.]

I favour the double tap. Childhood here saw chickenpox disturb something
Glandular fever in teenage years was the second "tap" smack bang when bodies are chemical soups..
It seemed like a viral tag team.
Do viral (and bacterial ) strains work together , if so which ones are known / prevalent and how do they fool the immune system

As we have varying onsets , the switches on the rails may differ , but are there common junctions?

There are also suppositions
The IDO hypothesis was founded where the loss / difference in genetic expression was not thought to matter as the other gene would cover it
Other pathways no doubt have such suppositions , would these also potentially factor in
Glutathione for example ?

ETA I have not read whole thread yet so this may be redundant

I caught a winter vomiting bug a couple of months into sixth form, and afterwards began to suffer from eczema, dizzyness and blood sugar 'crashes'. Struggled to get up for sixth form.

Then at 19 over the winter period I developed insomnia, hypersomnia when I actually did manage to sleep, and dpdr panic attack type issues. I no longer had my youthful energy. Iirc I caught a couple of bugs that winter.

Then at 26 I got strep throat and developed noticeable PEM.

There was also a lot of heavy drinking and a fair few head injuries, both of which can cause immune system shenanigans. So I think my experience, if the symptoms pre full onset at 26 were prodromal, would support a theory of successive immune hits gradually knocking you into into an ME/CFS state.

I know for certain I didn't have ME/CFS before sixth form becuase I was running and going to the gym every week and felt fine.