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Inflammation turns mitochondria into toxic factorie

natasa778

Senior Member
Messages
1,774
Breaking research discovers how macrophages turn mitochondria into toxic chemical-producing inflammation-promoters.

Macrophages (meaning "big eaters") are a type of white blood cell that engulf and digest cellular debris and foreign substances. These biological dustbins maraud within and between cells throughout the body, destroying pathogens as they roam.

Alongside their taste for microbes and other invaders, they play a substantial role in orchestrating the immune response. Macrophages stimulate the immune system and help to call it to action when necessary.

As part of this role, macrophages are known to promote inflammation. However, once the time has come for the inflammation response to stop, they switch roles, suppressing inflammation and busying themselves with repairing damaged tissue.

...

The investigators found that during the initial phase of the macrophage response, the cells alter the activity of mitochondria....

During inflammation, macrophages were found to halt mitochondria's production of energy and switch them to producing toxic compounds that further amplify inflammation.

...
"Mitochondria are well known as the key energy generators in our cells, but we found that during inflammation they switch from that role to instead making toxic products from oxygen using an enzyme called succinate dehydrogenase, which promotes inflammation."

http://www.medicalnewstoday.com/articles/313090.php
 

hixxy

Senior Member
Messages
1,229
Location
Australia
Original paper:

Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages

Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Däbritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O'Neill LA.

Abstract
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.

Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

KEYWORDS:
immunometabolism; innate immunity; macrophage; reverse electron transport; succinate; succinate dehydrogenase; toll-like receptors

https://www.ncbi.nlm.nih.gov/pubmed/27667687
http://www.cell.com/cell/fulltext/S0092-8674(16)31162-X
 

Paralee

Senior Member
Messages
571
Location
USA
Macrophages come from the monocytes that are one of the WBC's right?

I have had high monocytes for a long time, I know that's not right but dr after dr says that it's perfectly acceptable. I wish they'd take a ride in my body for just one day.
 

natasa778

Senior Member
Messages
1,774
excellent finding... establishes a bridge between immune and metabolic-mitochondria anomalies found of ME, which I'm sure do exist


This may or may not be relevant to rituximab effects in ME, but still interesting:

Rituximab therapy in refractory macrophage activation syndrome secondary to systemic lupus
erythematosus


Article is behind a paywall, no abstract. Here some bits:

Macrophage activation syndrome (MAS) is a life-threatening condition characterised by high fever,
pancytopenia, liver insufficiency and coagulopathy. Activation and uncontrolled proliferation of
lymphocytes and well-differentiated macrophages cause widespread haemophagocytosis and cytokine
overproduction. Systemic autoimmune disease has been reported to be the underlying disorder in
5% of cases of MAS ... Rituximab use has been mainly reported in MAS secondary to Epstein Barr virus (EBV) infection but not SLE...

[They go on to describe a patient with severe SLE that was unresponsive to any treatment until rituximab saved the day ]

MAS secondary to acute SLE in the absence of identifiable infection was established based on
laboratory, clinical and bone marrow findings.

...
The possible pathogenesis of MAS in SLE includes phagocytosis of haematopoietic cells
mediated by autoantibodies and immune complex deposition on bone marrow hematopoietic cells.

... Rituximab may therefore be an effective treatment in MAS secondary to SLE as a result of B
cell depletion causing decreased antigen presentation and disruption of T-cell co-stimulation.

Rituximab may be an effective treatment of SLE-related refractory MAS, although larger studies are
required to establish its use.
 

lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
This may or may not be relevant to rituximab effects in ME, but still interesting:

Rituximab therapy in refractory macrophage activation syndrome secondary to systemic lupus
erythematosus


Article is behind a paywall, no abstract. Here some bits:
the connection you made might very well be right... we deactivate the macrophages and the mitochondria can breathe again... I wonder how will the full book of ME look 100 years from now... I think this is analogous to the full book of our solar system (i'm interested in space exploration). 50 years from now, that book could show a solar system with a few extra Neptune sized planets on the far reaches of the system, many earth sized ones, and even one brown dwarf (failed star), we know so little yet...
 

HowToEscape?

Senior Member
Messages
626
"50 years from now, that book could show a solar system with a few extra Neptune sized planets on the far reaches of the system...."

That is rather unlikely, as we have telescopes based on land, in orbit around Earth AND on roving, space-traveling explorer craft which have reached the outer parts of our solar system. Any object as massive as a brown dwarf would affect the orbits of planets in the solar system, and its position could thus be calculated.
 
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lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
"50 years from now, that book could show a solar system with a few extra Neptune sized planets on the far reaches of the system...."

That is rather unlikely, as we have telecscopes based on land, in orbit around Earth AND on roving, space-traveling explorer craft which have reached past Neptune in our solar system. In the past 100 years, more exploration of the skies has been done than in the previous 10,000.
It would be nice if we'd put some more effort into exploring the mysteries of the medicine and less into government pickpocketing for one or the other favored constituency (speaking of USA).
well, it's very hard to cover the whole solar system, which expands to the oort cloud, half a light year away from the sun using current remote sensing technologies and probes. We might know a lot about the inner solar system but that's just a very little part of hte whole thing. Besides, since recently, there is very strong evidence for a ninth neptune size planet disrupting kuiper belt objects and other celestial bodies, look here: http://www.sciencemag.org/news/2016...eptune-sized-planet-lurks-unseen-solar-system
Regarding the futility of space exploration, even I who would give everithing I have for a single treatment for ME, think it is important. There're many things with "no practical benefit" that are useful for us humans, like games, sports, music, plastic arts, cloth designing, works of fiction, etc... We can just abandon everything not related to physical preservation, I think
 

HowToEscape?

Senior Member
Messages
626
well, it's very hard to cover the whole solar system, which expands to the oort cloud, half a light year away from the sun using current remote sensing technologies and probes. We might know a lot about the inner solar system but that's just a very little part of hte whole thing. Besides, since recently, there is very strong evidence for a ninth neptune size planet disrupting kuiper belt objects and other celestial bodies, look here: http://www.sciencemag.org/news/2016...eptune-sized-planet-lurks-unseen-solar-system
Regarding the futility of space exploration, even I who would give everithing I have for a single treatment for ME, think it is important. There're many things with "no practical benefit" that are useful for us humans, like games, sports, music, plastic arts, cloth designing, works of fiction, etc... We can just abandon everything not related to physical preservation, I think

I absolutely agree that some of humanity's most important pursuits are things that one can't buy, sell, eat or have otherwise "practical" benefit from. Cultures that valued only practical things stayed frozen. Even the Roman aqueducts and tunnels would not have been possible without Greek science and maths. I didn't mean at all to declare space exploration futile or un-neccesary. I've edited my previous post to remove such implication.
That's the first I've heard about a possible unknown planet, interesting.
 

lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
I absolutely agree that some of humanity's most important pursuits are things that one can't buy, sell, eat or have otherwise "practical" benefit from. Cultures that valued only practical things stayed frozen. Even the Roman aqueducts and tunnels would not have been possible without Greek science and maths. I didn't mean at all to declare space exploration futile or un-neccesary. I've edited my previous post to remove such implication.
That's the first I've heard about a possible unknown planet, interesting.
Sorry, maybe I misunderstood you since I'm not a native english speaker :)
If I remember correctly, the suggestion that there might be much more in the solar system due to perturbation in other bodies started with the discovery of Sedna, which has a very anomalous orbit. It is considered too in the calculation of this planet X orbit
 

HowToEscape?

Senior Member
Messages
626
Sorry, maybe I misunderstood you since I'm not a native english speaker :)
If I remember correctly, the suggestion that there might be much more in the solar system due to perturbation in other bodies started with the discovery of Sedna, which has a very anomalous orbit. It is considered too in the calculation of this planet X orbit
Well, with brain fog etc I don't write very clearly. Nothing wrong with your English. I also didn't know about Sedna, that's interesting. I s'pose this brain fog thing means there's quite a bit I don't know about.
 

lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
Well, with brain fog etc I don't write very clearly. Nothing wrong with your English. I also didn't know about Sedna, that's interesting. I s'pose this brain fog thing means there's quite a bit I don't know about.
Oh, we all know so little... I wished I could have go to college... :(
 

lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
Macrophages come from the monocytes that are one of the WBC's right?

I have had high monocytes for a long time, I know that's not right but dr after dr says that it's perfectly acceptable. I wish they'd take a ride in my body for just one day.

I just received the results of a blood test showing increased monocytes too, the normal range is 8% maximum and I got 19%. In previous blood works done over the years, they always were at the high limit, 8%, 9%, even 13%, but never 19%, this is happening for the first time.
 

Mary

Moderator Resource
Messages
17,335
Location
Southern California
I wonder if that shift could be responsible for that "feeling poisoned" feel which sometimes can suddenly kick in with us. This could be such a major breakthrough for us

When I have felt poisoned in the past (it hasn't happened for awhile), it's invariably connected to some form of detoxing or toxic overload so I literally am being poisoned. I never feel poisoned with plain old PEM.
 

lauluce

as long as you manage to stay alive, there's hope
Messages
591
Location
argentina
When I have felt poisoned in the past (it hasn't happened for awhile), it's invariably connected to some form of detoxing or toxic overload so I literally am being poisoned. I never feel poisoned with plain old PEM.
I feel the same, when I feel poisoned, I think I am actually poisoned!