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Oxidative metabolism and macrophage-mediated inflammation
Serenoa
Posted: Wednesday, November 23, 2016 5:46 AM
Joined: 4/24/2012
Posts: 483


This is a bit technical but the main point is that the immune system cells of the brain can promote both inflammation as well as healing, and that these functions are related to oxidative metabolism, various cellular molecules, and mitochondria. I think there are some good clues here.

Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation

 Summary

"Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARg-coactivator-1b (PGC-1b ) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1b primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1b attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation."


Lane Simonian
Posted: Wednesday, November 23, 2016 9:52 AM
Joined: 12/12/2011
Posts: 4782



I was just thinking about missing your posts. Have a Happy Thanksgiving, Serenoa.

This anti-inflammatory pathway is inhibited by the nitration in Alzheimer's disease.  There are also consequences for memory and energy production in the mitochondria.

Nitration of PPARQ inhibits ligand-dependent translocation into the nucleus in a macrophage-like cell line, RAW 264

http://onlinelibrary.wiley.com/doi/10.1016/S0014-5793(02)03059-4/pdf

 

Oxidative stress and inhibition of oxidative phosphorylation induced by peroxynitrite and nitrite in rat brain subcellular fractions.


 
 

 2008;22(1):1-14.

The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer's disease: therapeutic implications.

Abstract

Alzheimer's disease is a complex neurodegenerative disorder, with aging, genetic and environmental factors contributing to its development and progression. The complexity of Alzheimer's disease presents substantial challenges for the development of new therapeutic agents. Alzheimer's disease is typified by pathological depositions of beta-amyloid peptides and neurofibrillary tangles within the diseased brain. It has also been demonstrated to be associated with a significant microglia-mediated inflammatory component, dysregulated lipid homeostasis and regional deficits in glucose metabolism within the brain. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism, and is found in elevated levels in the brains of individuals with Alzheimer's disease. A recently appreciated physiological function of this type of receptor is its ability to modulate inflammatory responses. In animal models of Alzheimer's disease, PPARgamma agonist treatment results in the reduction of amyloid plaque burden, reduced inflammation and reversal of disease-related behavioural impairment. In a recent phase II clinical trial, the use of the PPARgamma agonist rosiglitazone was associated with improved cognition and memory in patients with mild to moderate Alzheimer's disease. Thus, PPARgamma may act to modulate multiple pathophysiological mechanisms that contribute to Alzheimer's disease, and represents an attractive therapeutic target for the treatment of the disease.

Oxidative phosphorylation defects and Alzheimer's disease.

Abstract

Abnormalities in cellular bioenergetics have been identified in patients with Alzheimer's disease (AD) as well as in patients with other neurodegenerative diseases. The most commonly reported enzyme abnormalities are in the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and oxidative phosphorylation (OXPHOS). Although genetic evidence supporting primary OXPHOS defects as a cause for AD is weak, functionally important reductions in OXPHOS enzyme activities appear to occur in AD and may be related to beta-amyloid accumulation or other neurodegenerative processes. Since reduced neuronal ATP may enhance susceptibility to glutamate toxicity, OXPHOS defects could play an important role in the pathophysiology of AD.

 


Serenoa
Posted: Thursday, November 24, 2016 8:36 AM
Joined: 4/24/2012
Posts: 483


Thank you Lane, happy T-Day to you too

From your post above:

"Nitration of PPARy inhibits ligand-dependent translocation into the nucleus in a macrophage-like cell line"
 

We are bringing together some good clues. PPARy may be a very central player in the inflammatory process. Macrophages, I believe, are the key. They can wear a black hat or a white hat, and there is evidence that they can change which hat they wear depending on various factors (like the influence of peroxynitrite).

We have made connections with PPARy before in the Cholesterol topic. Here is one of the articles in those posts:

A PPARy-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis

This is from Wikipedia:

 "Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPARy is activated by prostaglandin and certain arachidonic acid metabolites."

There is much more evidence to post...
Lane Simonian
Posted: Friday, November 25, 2016 10:05 AM
Joined: 12/12/2011
Posts: 4782


I had forgotten about how the nitration of PPAR leads to the buildup of cholesterol in the brain which may be a factor in the progression of Alzheimer's disease.  And PPAR inhibition may contribute to inflammation in Alzheimer's disease.

I need to change one of the posts above as it was initially for PARP rather than for PPAR.

We stayed home for Thanksgiving because of snow in the mountains but we still had a good Thanksgiving.  I hope that you and your family did as well.

Keep the good post coming.


Serenoa
Posted: Thursday, December 8, 2016 6:00 PM
Joined: 4/24/2012
Posts: 483


"Stimulation of PPARy by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARy agonists, therefore PPARy represents an attractive therapeutic target for the treatment of AD."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263458/

 

"The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism, and is found in elevated levels in the brains of individuals with Alzheimer's disease. A recently appreciated physiological function of this type of receptor is its ability to modulate inflammatory responses. In animal models of Alzheimer's disease, PPARgamma agonist treatment results in the reduction of amyloid plaque burden, reduced inflammation and reversal of disease-related behavioural impairment. In a recent phase II clinical trial, the use of the PPARgamma agonist rosiglitazone was associated with improved cognition and memory in patients with mild to moderate Alzheimer's disease."

https://www.ncbi.nlm.nih.gov/pubmed/18072811

 

"Here we have investigated whether PPARy is nitrated in macrophage-like RAW 264 cells and the effect of nitration on the trans-location of PPARy into the nucleus. Western blot analysis showed that tumor necrosis factor, lipopolysaccharide or per-oxynitrite treatment signifcantly increases the nitration of PPARy."

http://onlinelibrary.wiley.com/doi/10.1016/S0014-5793(02)03059-4/pdf