Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

[bobbler]

AI

Is C6S found on the surface of neurons?

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

I’m getting possible complex links between this and iron regulation but risk it could be nonsense because on one bullet it say heparin can act as as strong an inhibitor as Hepcidin for iron, then another bullet notes heparin-iron complexes are being developed as novel approaches to anemia. Ok it seems it suppresses hepcidin so that’s how both could logically make sense.

 

[Jonathan Edwards]

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

It might be heparan sulphate rather than heparin. I doubt there is any link.
Googling quickly suggests that there isn't a heparin sulphate.

 

[V.R.T.]

An unexpected result:

IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself (J. Exp. Med, February 2026)

Sticky memories of an activated macrophage (associated commentary)

So does this paper suggest that if IFN-y is driving MECFS, JAK-STAT inhibitors might work to break the signalling loop?

 

[Jonathan Edwards]

So does this paper suggest that if IFN-y is driving MECFS, JAK-STAT inhibitors might work to break the signalling loop?

Put like that, maybe, but with an if and a might. (I am not sure whether there are complexities that mean it depends on which inhibitor we are considering.)

 

[Utsikt]

Put like that, maybe, but with an if and a might. (I am not sure whether there are complexities that mean it depends on which inhibitor we are considering.)

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

From the commentary:

Using a reductionist yet relevant model of human monocyte-derived macrophages stimulated acutely with IFN-γ, they found that long-term maintenance of de novoformed enhancers relied on continued signaling by the JAK–STAT pathway—even if the cytokine was washed out by replacing the culture medium. Inhibition of JAK1/2 with ruxolitinib in cells that were acutely stimulated with IFN-γ and later kept in fresh medium resulted in the loss of H3K4me1 and reduced chromatin accessibility at IFN-γ–induced enhancers (see panel A in figure). Removal of the JAK inhibitor rapidly restored STAT1 phosphorylation, indicating persistent IFN-γ signaling beyond the period of overt cytokine stimulation.

 

[V.R.T.]

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

From the commentary:

So perhaps the IFN-y itself would have to be targeted in this hypothetical situation? Are there drugs that do that?

 

[Jonathan Edwards]

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

Somewhere else I think it implies that if there is not continued signalling the IFN-g goes away. A bit confusing. I suspect that kinase inhibition for long enough (days or weeks?) might do the job.

But I can see this may only be part of the story and that for neurons, for instance, other signalling shifts might kick in.

But it would be worth knowing whether there is any information about from other uses of inhibitors that might give clues is to whether there might be a role in ME/CFS.