Targeting ‘Broken’ Metabolism in Immune Cells Reduces Inflammatory Disease

[edawg81]

Surprised this wasn't already posted:

Targeting ‘Broken’ Metabolism in Immune Cells Reduces Inflammatory Disease

http://www.scienceandtechnologyrese...sm-immune-cells-reduces-inflammatory-disease/

In a study published this week in the journal Nature Communications, they explain how blocking a single enzyme enabled them to reprogram macrophages – the immune cells which are activated in inflammatory conditions – to calm their activity and reduce inflammation in rats and mice with human-like disease.

At the heart of the research is the Krebs cycle, a complex loop of reactions which cells use to feed on sugar and generate molecules of ATP, the universal energy currency for cells.
​

Looks like this is decent evidence of a link between the immune system and energy issues that could be associated with ME CFS. I'm too foggy at the moment to figure it all out and comment.
So tag smart people. @nandixon @Hip @Jonathan Edwards

Full article:
http://www.nature.com/articles/ncomms16040

Thanks in advance for anyone that can comment on this.

 

[adreno]

“In immune cells that have to fight invaders, the metabolism is diverted from its usual cycle to make compounds that fight microbes,” explainedDr Jacques Behmoaras, from the Department of Medicine at Imperial, who led the research.

Dr Behmoaras added: “What we have found is that there’s an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds. If you block that enzyme, you block that specific branch of their metabolism, and make the cells cause less damage during inflammation.”

Could this potentially be the "off switch" we are looking for? It has been postulated that our metabolism is dysfunctional because it's directed at fighting invaders - stuck in fight mode- exactly like the article mentions.

So for us it might not be so much the reduction in inflammation that is interesting, but more the redirection of metabolical resources back to producing energy.

 

[aaron_c]

It would be ironic if QMUL contributed to an actual cure for this disease. Ironic in a very very good way.

 

[ebethc]

1. How is this therapy different than taking Branched Chain Amino Acids? Is this article saying there is a metabolic error in processing BCAA's? Not sure that adding more BCAA's would help in that case.

2. The full article is over my head for the most part, but there were some interesting statements on the role of LPS. I wish the interpreted article connected the dots a little better between Leaky Gut -> LPS -> misfiring macraphages. Can anyone here clarify re how leaky gut might influence this chain of events?

3. Parts of the full article seems to complement Ron Davis' work re excessive metabolites showing up in tests (I believe he said that Whitney's excessive metabolites were 2 standard deviations away from normal), but, again, I'm far from fluent in chemistry... Can anyone here explain? One example below.. @Janet Dafoe (Rose49)

• "Macrophages activated by LPS also show accumulation of Krebs cycle intermediates, such as succinate, regulating Hif-1α-mediated IL-1β production14. "

4. RIP RichVank (again).... He would be all over this

 

[Murph]

I don't have a science background but, thanks to ME/CFs, have attained a certain level of comprehension when it comes to scientific papers.... However, that paper is one of the most complex and reader-unfriendly things I have ever tried to understand!!

 

[Murph]

Footnote 33 to the paper leads here though:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814543/

A very comprehensive and much more readable summary of immune-metabolic links!

 

[adreno]

The full article is over my head for the most part, but there were some interesting statements on the role of LPS. I wish the interpreted article connected the dots a little better between Leaky Gut -> LPS -> misfiring macraphages. Can anyone here clarify re how leaky gut might influence this chain of events?

I think you summed it up pretty well yourself. LPS activates macrophages. Leaky gut means more endotoxins in the bloodstream. The connection is clear enough.

 

[AdamS]

They used an experimental compound called ERG240, developed by Ergon Pharmaceuticals, a small biotech company based in the US. ERG240 resembles the amino acid leucine, one of the building blocks of proteins, which is linked together by BCAT1. By flooding the cells with ERG240 they were able to jam up BCAT1 and block its action, so stopping the metabolism being diverted and ‘fixing’ the broken Krebs cycle. What’s more, the compound was effective in animal models of inflammation, without toxic side effects

Leucine has been mentioned on these forums a few times before. I guess there could be good reason for energy being diverted though if Leaky Gut is present.

 

[ebethc]

I think you summed it up pretty well yourself. LPS activates macrophages. Leaky gut means more endotoxins in the bloodstream. The connection is clear enough.

Right, but if that's the case, then why is the focus on manipulating the enzyme and not on fixing leaky gut and supplementing w BCAA's until your gut is healed? Is the enzyme broken solely because of LPS? Are they just going down this path to sell drugs? It's not clear...

I'm just going to keep working on leaky gut and get some BCAA's!

 

[adreno]

Right, but if that's the case, then why is the focus on manipulating the enzyme and not on fixing leaky gut and supplementing w BCAA's until your gut is healed? Is the enzyme broken solely because of LPS? Are they just going down this path to sell drugs? It's not clear...

It's probably just because they are immunologists, and blocking an enzyme is a more simple solution. And the drug angle, too. Besides, no one really knows how to get gut health back on track in a reliable way.

 

[ebethc]

It's probably just because they are immunologists, and blocking an enzyme is a more simple solution. And the drug angle, too. Besides, no one really knows how to get gut health back on track in a reliable way.

yep... the challenge of a multi-system illness is that each specialist looks at the illness through their own narrow training (a psychiatrist will tell you to do GET, an immunologist will develop drugs to turn off an enzyme... God knows what else turning off an enzyme will do!, a rheumatologist will put you on enbrel, etc.)

 

[pattismith]

3. Parts of the full article seems to complement Ron Davis' work re excessive metabolites showing up in tests (I believe he said that Whitney's excessive metabolites were 2 standard deviations away from normal), but, again, I'm far from fluent in chemistry... Can anyone here explain? One example below.. @Janet Dafoe (Rose49)

• "Macrophages activated by LPS also show accumulation of Krebs cycle intermediates, such as succinate, regulating Hif-1α-mediated IL-1β production14. "

The original article quoted is this one:

Succinate is an inflammatory signal that induces IL-1β through HIF-1α
10 April 2013
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis1.
Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages

A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate.

Glutamine-dependent anerplerosis is the principal source of succinate, although the ‘GABA (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target.
Lipopolysaccharide also increases succinylation of several proteins.
We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

on the same topic, I found this paper:

GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis
2016
Abstract
When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate.
In this study, we show that during this activation, macrophages release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine and paracrine sensor for extracellular succinate to enhance IL-1β production.
GPR91-deficient mice lack this metabolic sensor and show reduced macrophage activation and production of IL-1β during antigen-induced arthritis. Succinate is abundant in synovial fluids from rheumatoid arthritis (RA) patients, and these fluids elicit IL-1β release from macrophages in a GPR91-dependent manner. Together, we reveal a GPR91/succinate-dependent feed-forward loop of macrophage activation and propose GPR91 antagonists as novel therapeutic principles to treat RA.

on the other hand Succinate seems to be deficient in ME patients!

http://forums.phoenixrising.me/inde...-tca-cycle-can-we-boost-it.50465/#post-832226