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Specific PKC isoforms regulate LPS-stimulated iNOS induction in murine microglial cells
Serenoa
Posted: Friday, June 21, 2013 7:09 AM
Joined: 4/24/2012
Posts: 484


 

As I find out more about how microglia (i.e. the immune system) affect neurodegeneration, I asked the question: what is the relationship of these activated microglia to the PKC (protien kinase C)-initiated pathway which leads to oxidative dammage. And, here is a clue. Activated microglia work through PKC to produce the damaging mediators like nitrous oxide. Therefore, microglial activation is upstream of PKC, meaning microglial activation comes first.

 

Specific PKC isoforms regulate LPS-stimulated iNOS induction in murine microglial cells

 http://www.jneuroinflammation.com/content/8/1/38

  

"Murine microglia expressed high levels of nPKCs, and expressed relatively low levels of cPKCs and aPKCs. All PKC inhibitors attenuated induction of iNOS in LPS-activated microglia. Knockdown of PKC δ and PKC β attenuated ERK1/2 and p38 phosphorylation, respectively, and blocked NF-κB activation that leads to the expression of iNOS in reactive microglia (Wen, 2011)."

 

 

Now here's something else interesting. Microglia have varying activation states, some good and some bad. Activating microglia in a good way may avoid the PKC pathway and thus stop the cause of neurodegeneration.

 

Assessing activation states in microglia

http://www.ncbi.nlm.nih.gov/pubmed/20205642

 

"Since the original identification of microglia as a principal player in the brain's innate immune response, microglial activation has been widely studied. Recent studies suggest that microglial responses are heterogeneous, requiring a more precise definition of the functional outcomes of their participation in disease. Similarly to other tissue macrophages, microglia respond to inflammatory or injurious stimuli in the CNS in a pre-programmed manner that is designed to both kill and to set the stage for repair and resolution of the disease."

 


Lane Simonian
Posted: Friday, June 21, 2013 11:41 AM
Joined: 12/12/2011
Posts: 5158


This is so close to it. Thanks for the great article and analysis, Serenoa.  Peroxynitrites (via the combination of inducibe nitric oxide and superoxide anions) can lead to the activation of microglia and the activation of microglia can lead to the formation of peroynitrites.  Block the activation of phospholipase C, protein kinase C, MAPK kinases--particularly p38 MAPK, or inducible nitric oxide synthase and you prevent or limit neurodegeneration.  As you note, not all microglial activation is harmful, sometimes it may actually be helpful, but when it is linked to peroxynitrite formation it plays a key role in Alzheimer's disease. 
Serenoa
Posted: Friday, June 21, 2013 2:58 PM
Joined: 4/24/2012
Posts: 484


Well then, it seems we may have a workable two-fold strategy: First inhibit and scavenge peroxinitrites currently in the brain using antioxidants/peroxinitrite scavengers;

 

Second, reprogram the microglia (immune system) in the brain to stop producing nitrous oxide, iNOS peroxinitrite and other damaging compounds and start producing neuroprotective factors.

 

I think the first part is supported by the research (as you have posted so much of), but the second part is not so clear. Mostly I think there is evidence for GM-CSF doing this, but not all the research supports it.


Lane Simonian
Posted: Saturday, June 22, 2013 12:37 AM
Joined: 12/12/2011
Posts: 5158


Yes, this is where it gets murky for me, too. I have been searching today for the pathway or pathways by which activated microglia produce inducible nitric oxide and then peroxynitrites and this is the best that I have come up with so far. 


 

http://www.jneurosci.org/content/27/18/4957.full.pdf 

 

http://www.ncbi.nlm.nih.gov/pubmed/18523309 

 

http://www.jneuroinflammation.com/content/2/1/20 

 

http://www.ncbi.nlm.nih.gov/pubmed/17086106 

 

So perhaps the inhibition of purinergic receptors along with peroxynitrite scavengers may help protect neurons in Alzheimer's disease.  Granulocyte macrophage colony stimulating factor may help in activating  the right microglia, but you are right in saying the evidence for this is not conclusive. 


Geo
Posted: Saturday, June 22, 2013 2:16 AM
Joined: 6/20/2012
Posts: 34


Cinnamon extract has come up a few times lately and this study specifically examines its effect on microglia and possible blocking of NG-kB activation.

 

Inhibition of neuroinflammation by cinnamon and its main components.

Abstract

Uncontrolled activation of microglia contributes to neuroinflammation, which is highly involved in the development of neurodegenerative diseases. Although cinnamon has neuro-protective properties, its capacity to inhibit neuroinflammation has not been investigated and its active compounds remain unclear. Therefore, the composition of cinnamon extract was analysed by LC-MS and the ability of cinnamon and its main constituents to inhibit neuroinflammation was evaluated using a lipopolysaccharide (LPS)-activated BV2 microglia culture system. In total, 50 μg/mL cinnamon extract decreased significantly the production and expression of nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in LPS-activated BV2 microglia. Blocking of nuclear factor-κB (NF-κB) activation was the most likely mechanism responsible for inhibition by cinnamon of neuroinflammation. Among the eight tested compounds, cinnamaldehyde had the greatest anti-neuroinflammatory capacity. Experimental results suggest that cinnamon may have a potential therapeutic effect against neurodegenerative diseases and its potent anti-neuroinflammatory capacity was primarily attributed to cinnamaldehyde.

http://www.ncbi.nlm.nih.gov/pubmed/23497886


Serenoa
Posted: Saturday, June 22, 2013 6:19 AM
Joined: 4/24/2012
Posts: 484


Thanks Land and Geo. Looks like some great info, I will have time to review later. Let me just throw this out for now. New study on IL-34. This may be evidence that M-CSF works to activate microglia in a good way, but GM-CSF does not.

 

IL-34 Induces the Differentiation of Human Monocytes into Immunosuppressive Macrophages. Antagonistic Effects of GM-CSF and IFNγ

IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (Mφ) or dendritic cells (DC). A wide spectrum of Mφ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14high CD163high CD1a− Mφ (IL-34-Mφ). Upon LPS stimulation, IL-34-Mφ exhibit an IL-10high IL-12low M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-Mφ exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-Mφ are phenotypically and functionally similar to M-CSF-Mφ. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive Mφ. Moreover, the generation of IL-34-Mφ is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFNγ and GM-CSF prevent the generation of immunosuppressive Mφ induced by IL-34. IFNγ also switches established IL-34-Mφ into immunostimulatory Mφ. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFNγ and GM-CSF prevent this effect.

 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0056045#pone.0056045-Greter1

 

 


Lane Simonian
Posted: Monday, June 24, 2013 11:11 AM
Joined: 12/12/2011
Posts: 5158


These macrophage colony stimulating factors are frustrating characters.  Here is one to the negative. 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181600/ 

 

Whether the anti-inflammatory version of the macrophage colony stimulating factor can operate in Alzheimer's disease is not clear. 

 

http://www.sciencedirect.com/science/article/pii/S0171298510000860 

 

http://www.ncbi.nlm.nih.gov/pubmed/12057765 

 

As Geo aptly notes cinnamon reduces inflammation by inhibiting Nuclear factor-kappa B.  Other spices do the same thing. 

 

 2004 Dec;1030:434-41.

Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning.

Source

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org

Abstract

The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S-allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning."

 

Eugenol in true cinnamon leaf and clove essential oil may be the most effective anti-inflammatory and peroxynitrite scavenger. 

 

http://onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.2011.01440.x/abstract 

http://www.ncbi.nlm.nih.gov/pubmed/15941312 

 

 

 

 

 

 

 


Serenoa
Posted: Tuesday, June 25, 2013 9:00 AM
Joined: 4/24/2012
Posts: 484


Fascinating! We are getting so close. I think this M1, M2 microglia activation business is very important. I wish I had more time to study this right now. Thank you for those links.

Lane Simonian
Posted: Tuesday, June 25, 2013 3:56 PM
Joined: 12/12/2011
Posts: 5158


Yes, very close now.  The anti-inflammatory activities of the M2 (macrophage- colony stimulating factor) is regulated by heme oxygenase but heme oxygenase is deactivated by peroxynitrites. 


 

http://www.biomedcentral.com/1471-2210/4/26 


 

The combination of a peroxynitrite scavenger with macrophage-colony stimulating factor may provide an effective anti-oxidant/anti-inflammatory approach to Alzheimer's disease. 


Serenoa
Posted: Thursday, June 27, 2013 8:54 PM
Joined: 4/24/2012
Posts: 484


There seems to be a zinc connection with GM-CSF/immune system regulation. Anyone know how zinc affects the immune system? Is a zinc deficiency involved with neuron damage due to activated macrophages/microglia?

 

Here's one study showing a connection:

 

 

Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses.

 

http://www.ncbi.nlm.nih.gov/pubmed/20731582