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

It's not inhibiting it's own metabolism per se, but rather shifting towards glycolysis which can be mobilized much more quickly, even if it is less efficient in terms of ATP produced per glucose molecule. If there's an adequate supply of glucose, the macrophage is still able to produce more than enough ATP for its own purposes. If there's not, then it might have issues.

 

I for one am open to the idea of an adaptive immune shift, though I think metabolism is the link that could define a positive feedback loop. Given that a shift to aerobic glycolysis seems to be necessary for interferon gamma production (at least in NK cells and CD8s, from what I've been reading), I am wondering about the possibility of a continuous feedback loop between macrophages and some lymphocyte population.

i.e. Lymphocyte releases interferon gamma, which when combined with some other stimulus causes [edit: some metabolic reprogramming in macrophages that causes them] to release a factor that encourages aerobic glycolysis in the lymphocytes, which then continue to produce more interferon gamma despite the absence of a continued upstream stimulus.

This theory, however, relies on metabolic reprogramming in the lymphocytes being necessary and sufficient for interferon gamma production. If this is the case, then the main question becomes: how is this feedback loop normally turned off in healthy individuals, and why isn't that off switch getting triggered in ME?

 

That isn't the way it comes across from Phair. He talks of the cell shutting down - to 43% of capacity or some such. To protect itself from providing any fuel for viral growth.


At least in the context of inflammation in rheumatoid arthritic joints one of the earliest observation sis that glucose levels approach zero! Which is probably why cartilage dies.

 

If he's speaking about the macrophage itself shutting down then I think that's where the hypothesis would need to be amended--macrophages become quite metabolically active during infection, and as you said, the goal would be impairing other nearby cells.

 

Hang on, I've already patented that.

 

That's my thinking. I like several aspects of the model but I don't feel it is 'situated' in the context of tissue geometry and cell types I am familiar with.

This is the sort of dialogue I think goes places.

 

Yeah, looks like they're just getting ready. The link's live.

 

I seem to have a habit of arriving to a new topic (for me) and coming up with brilliant ideas just before reading the paper that spelled it out several years ago.

Are you referring to rituximab? If so, do you think B cells are involved here or another cell type?

 

Preferential glucose sequestration by greedy activated macrophages?

 

No, I was promised that I would be cited as inventor on the rituximab for RA patent but they diddled me. I lost out on several million, maybe tens of millions. But I never wanted the money (I got the sun in the morning... band plays...) and made a few hundred grand out of providing legal advice to other companies who managed to get the patent quashed! (And other patents once I had got a reputation for keeping cool in the witness box.) Genentech asked me to be on their side for £120K but they screwed up their evaluation of the situation. They should have coughed up when I asked for 500K some years earlier.

But that is all distant past. To answer the question, I am going to suggest that B cells are involved indirectly. This is to finesse some epidemiological puzzles. It is probably wrong but I like the exercise. All will become clear fairly soon I hope.

 

Or just using it up. To be honest it will probably be mostly neuts.

 

Don't worry. Two wrongs don't make a right but in science one wrong reveals a right instead. At least that is the way I have always worked. Somebody else is going to come up with the knock down data - very likely a member here. I am just trying to keep the kettle boiling in the meantime.

 

By knock down data do you mean like the knock your socks of eureka moment data? Or something else.

Also are you saying that the particular pathway step in your theory involving b cells is likely wrong or the entire thing?

I must admit I'm on tenterhooks over the whole thing!

 

As in knocking down a specific gene in a cell line or mouse to see how it functions without the protein from that gene

 

https://en.m.wikipedia.org/wiki/Gene_knockdown

Ah interestingly I googled the phrase, came up with this and decided it wasn't relevant! But clearly it was

Thank you for clarifying!

 

To paulendat's earlier point, I've found this paper:
https://www.nature.com/articles/s41598-020-80933-7

Which shows that endogenous itaconate does not seem to stimulate interferon gamma in cytotoxic T cells. Inhibition of SDH by another exogenous agent, however, did enhance interferon gamma production in pre-activated T cells. Which really makes me want to see what if anything is bound to SDH in ME/CFS T cells...

 

I enjoiyed the talk, however most of the talk was above my understanding. The key part for us thinking about PEM seems to be that Itaconate has a delayed build-up in Macrophages after priming with LPS and other "stimulants" in the experiment.



The paper of this thread showed that peroxiredoxin 5 is inhibited (and likely other peroxiredoxins). Peroxiredoxin is an anti-oxidant and when it is suppressed ROS increases. It therefore could cause other antioxidants to be used up more quickly. Once they get used up the cell has trouble tamping down the ROS. They suspect that the reason the Itaconate mechanism is highly preserved across species is that boosting ROS is used for anti-pathogen defense.

The experiments also showed that Mitochondrial ROS was important part of the immunoregulation (the details went over my head).

Please correct me where I went wrong.