Glycolysis, infections and autoimmunity

[Gondwanaland]

https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201646477
Eur J Immunol. 2017 Jan;47(1):14-21. doi: 10.1002/eji.201646477. Epub 2016 Dec 21.
Lactate at the crossroads of metabolism, inflammation, and autoimmunity.
Pucino V1, Bombardieri M1, Pitzalis C1, Mauro C1.
Author information
1
William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.

Abstract
For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early '90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this "stop migration signal" is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4+ T cells to an IL-17+ subset, and reduces the cytolytic capacity of CD8+ T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.

Med Hypotheses. 2018 Jan;110:1-8. doi: 10.1016/j.mehy.2017.10.024. Epub 2017 Oct 26.
Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease.
Maccallini P1, Bonin S2, Trevisan G3.
Author information
1
Department of Mechanical Engineering, Sapienza University of Rome, Rome, Italy.
2
DSM-Department of Medical Sciences-Unit of Dermatology-University of Trieste, Trieste, Italy. Electronic address: sbonin@units.it.
3
DSM-Department of Medical Sciences-Unit of Dermatology-University of Trieste, Trieste, Italy.

Abstract
Some patients with a history of Borrelia burgdorferi infection develop a chronic symptomatology characterized by cognitive deficits, fatigue, and pain, despite antibiotic treatment. The pathogenic mechanism that underlines this condition, referred to as post-treatment Lyme diseasesyndrome (PTLDS), is currently unknown. A debate exists about whether PTLDS is due to persistent infection or to post-infectious damages in the immune system and the nervous system. We present the case of a patient with evidence of exposure to Borrelia burgdorferi sl and a long history of debilitating fatigue, cognitive abnormalities and autonomic nervous system issues. The patient had a positive Western blot for anti-basal ganglia antibodies, and the autoantigen has been identified as γ enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase. Assuming Borrelia own surface exposed enolase as the source of this autoantibody, through a mechanism of molecular mimicry, and given the absence of sera reactivity to α enolase, a bioinformatical analysis was carried out to identify a possible cross-reactive conformational B cell epitope, shared by Borrelia enolase and γ enolase, but not by α enolase. Taken that evidence, we hypothesize that this autoantibody interferes with glycolysis in neuronal cells, as the physiological basis for chronic symptoms in at least some cases of PTLDS. Studies investigating on the anti-γ enolase and anti-Borrelia enolase antibodies in PTLDS are needed to confirm our hypotheses.

http://science.sciencemag.org/content/360/6387/377
Science 27 Apr 2018:
Vol. 360, Issue 6387, pp. 377-378
DOI: 10.1126/science.aat4984

Disrupting metabolism to treat autoimmunity
Mai Matsushita1, Edward J. Pearce1,2
1Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
2Faculty of Biology, University of Freiburg, Freiburg, Germany.

Summary

Autoimmune and inflammatory diseases are diverse conditions caused by inappropriate and prolonged activation of immune cells with associated ongoing production of inflammatory mediators that cause tissue damage. In 2013, dimethyl fumarate (DMF), a methyl ester of fumaric acid used to treat psoriasis (an autoimmune skin condition), was approved for the treatment of multiple sclerosis (MS), a demyelinating autoimmune disease (1). Although this drug is now first-line treatment for relapsing remitting MS, its mechanism of action is elusive (1, 2). On page 449 of this issue, Kornberg et al. (3) provide evidence that the beneficial effects of DMF are related to its ability to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH)—a central enzyme in glucose metabolism (glycolysis)—and, in so doing, inhibit the development and function of inflammatory immune cells, highlighting the promise of targeting metabolism to modulate immune responses. >>>> See below<<<<<

http://science.sciencemag.org/content/360/6387/449
Science. 2018 Apr 27;360(6387):449-453. doi: 10.1126/science.aan4665. Epub 2018 Mar 29.
Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity.
Kornberg MD1, Bhargava P1, Kim PM2, Putluri V3, Snowman AM4, Putluri N3,5, Calabresi PA1,4, Snyder SH6,4,7.
Author information
1
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. ssnyder@jhmi.edu.
7
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract
Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, thereby presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate (DMF), a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, DMF covalently modifies cysteine residues in a process termed succination. We found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzymeglyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo. It thereby down-regulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our results provide mechanistic insight into immune modulation by DMF and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

 

[sb4]

@Gondwanaland "We found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzymeglyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo. It thereby down-regulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects."

So is this perhaps the reason that ketogenic diets can improve autoimmune conditions?

I wonder if you could supplement other versions of fumurate and they would have the same affect on GAPDH, probably not.

 

[frozenborderline]

Wow this looks really interesting and up my alley. Will take a look at it when (fingers crossed) recovered from this crash