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

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Abstract
The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and on mitochondrial reactive oxygen species.

We find that itaconate non-covalently inhibits peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages.

The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate.
LINK - paywall

Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.
 
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From one of the authors of this paper:

latest from our lab: ITACONATE MECHANISM SOLVED!! Tom Paulenda
@tompaulenda

Tom solved molecular mechanism of immunoregulatory action of itaconate in macrophages.

Previously, our lab has discovered two major immunoregulatory phenotypes of itaconate in macrophages - enhancement of type I interferon signaling and inhibition of late inflammasome activation (Swain et al, 2020 and Bambouskova et al, 2021). Yet the mechanism of immunoregulation itaconate has been elusive even though we (and others) have previously shown its ability to inhibit Sdh and its mild electrophilic properties.

In the latest work, we believe we have finally cracked that puzzle!! We show that both immunoregulatory phenotypes are driven by the ability of itaconate to modulate ROS through non-covalent inhibition of the peroxiredoxin 5, mitochondrial peroxide-detoxifying enzyme.

We describe major new phenotypes for the pro-interferon action of itaconate in vitro and in vivo and show that Prdx5 inhibiton is sufficient for immunoregulatory action of itaconate and does not require neither Sdh inhibition nor its mild electrophilicity.

https://twitter.com/user/status/1913207834340163955
 
Toll-like receptors identify some evidence of a pathogen. They up regulate the production of itaconate.
Itaconate blocks the TCA cycle, the process that makes ATP out of glucose.
Itaconate also blocks PRDX5 (peroxiredoxin 5) which means that the peroxide (H2O2) isn't mopped up.
Increased peroxide contributes to interferon production.

Interferon has been used as a hepatitis B treatment, reducing viral loads. But the treatment has side effects, including symptoms that seem to be similar to ME/CFS.

____________

DNA is ejected into the cytosol during viral infection and invasion by some intracellular bacteria.
The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.
STING is the protein Stimulator of Interferon Genes
H2O2 can up regulate STING, resulting in interferon.

But, it looks like itaconate can also inhibit the CGAS-STING pathway. So, clearly, it's complicated*. Perhaps some of the checks and balances have gone awry in ME/CFS?

* Edit to add: See paulendat's explanation below that the differences in reported itaconate function in the literature relate to natural itaconate and derivates used in the lab
 
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See for example here: [Edit - ignore this - seems to be for an Itaconate derivative, not actual Itaconate, see next post]
Scientists discover promising ‘off-switch’ for inflammatory diseases
We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate.

Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons
Click to expand...
 
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Hi I'm Tom, lead author of the itaconate Prdx5 story. I would suggest Caution with relation of itaconate and inhibition of type I interferon (IFNa and IFNb).

Research of itaconate often heavily relies on the itaconate derivatives like dimethyl itaconate (DI) or 4-octyl itaconate (4OI). Important difference between natural itaconate and its derivatives is their electrophilicity. Itaconate is a weak electrophole while derivatives are strong electrophiles. This means derivatives have high Affinity to permanently modify proteins.
Strong electrophiles are potent activator of NRF2 pathway, that inhibits interferon production. However, natural itaconate being a weak electrophile only contributes to NRF2 activation upon LPS activation. In the light of our recent discovery I believe it is only dye to higher production of ROS, rather than itaconate directly activating NRF2 through KEAP1 alkylation like DI or 4OI.

Here is paper on comparison of derivatives
https://pubmed.ncbi.nlm.nih.gov/32694786/
 
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The same applies to the inhibition of cGAS/STING pathway. It is not itaconate, but derivatives that were shown to modify STING and inhibit it's activity.

This is one thing artyomov lab has been heavily pushing, to abandon derivatives and study natural itaconate or at least stop using derivatives as proxy for natural itaconare.
 
paulendat said:
Hi I'm Tom, lead author of the itaconate Prdx5 story. I would suggest Caution with relation of itaconate and inhibition of type I interferon (IFNa and IFNb).

Research of itaconate often heavily relies on the itaconate derivatives like dimethyl itaconate (DI) or 4-octyl itaconate (4OI). Important difference between natural itaconate and its derivatives is their electrophilicity. Itaconate is a weak electrophole while derivatives are strong electrophiles. This means derivatives have high Affinity to permanently modify proteins.
Strong electrophiles are potent activator of NRF2 pathway, that inhibits interferon production. However, natural itaconate being a weak electrophile only contributes to NRF2 activation upon LPS activation. In the light of our recent discovery I believe it is only dye to higher production of ROS, rather than itaconate directly activating NRF2 through KEAP1 alkylation like DI or 4OI.

Here is paper on comparison of derivatives
https://pubmed.ncbi.nlm.nih.gov/32694786/
Click to expand...

So are you saying that there may not be as strong of a relationship between itaconate and type 1 interferon as other studies suggest because they use itaconate derivatives rather than natural itaconate?

Braganca said:
https://twitter.com/user/status/1913655586467545544
Click to expand...


Could you elaborate on the great potential for connection you see between your work and ME/CFS
 
@V.R.T.
No I'm saying the exact opposite. Itaconate boosts Type I IFN production in activated macrophages as we showed both in vitro and in vivo.

I'm saying that itaconate derivatives do the exact opposite. But you will not find the derivatives inside the cells or your body. That's the main difference.

Problem is that people confuse (scientist s are the reason) natural itaconate and it's derivatives.

Let me know if this clarifies it or if I should do better.
 
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