Macrophage Polarization and IDO Enzymes, Immunity, Cancer and Depression



Macrophage Polarization and IDO Enzymes, Immunity, Cancer and Depression
Feb. 5th 2020

The subject of macrophage polarization has many practical applications in treating immune dysfunction in diseases like cancer, diabetes, chronic fatigue, AIDS, sepsis and any diseases with fibrosis occurring.
Macrophages or our white blood cells respond to an enzyme called Indoleamine-2,3-dioxygenase (IDO) and change.
IDO is a type of signal used by baby cells, wound cells or any new cells to tell the M1 macrophages to avoid any area of repair and not gobble it up.
Hence cancer cells releasing IDO can avoid our own immune system and stay alive.

To summarise a complex subject, our white blood cells (macrophages) have 2 types.
M1 macrophages get in and dig out rubbish whether it is old collagen or infections from bacteria and fungus, cancer cells or fat cells.
The other types are M2 macrophages, they seem to have 2 functions, one is to dig out large scale infections such as TB and malaria or anything big stuck in the body, a fungal infection or a solid object can cause an M2 reaction.
To do this the baby macrophages bind together like a rugby scrum and these are called giant cell multinucleated macrophages, they also work with other immune cells to deposit collagen for repairing damaged areas of the body.
If there is a large infected area say with TB, fungus or malaria the white blood cells encircle the area first with collagen like a wall and then pour peroxide and nitric oxide in to dissolve everything and kill it.
To become M2 macrophages or bind together into the ‘rugby scrum type’ the white blood cells use our own retroviruses to fuse together into the giant multinucleated cells.

In the last decade retroviruses have been found to fuse sperm and eggs, they are needed in pregnancy, are used fuse osteoclasts to remove bone and fuse muscles together so our retroviruses have function in immune activity and structure.
When cancer occurs the tumours release IDO which in effect tells the immune system to leave the cancer cells alone.
Much worse than that is the white blood cells then become M2 macrophages, the macrophages get confused and fuse to the tumour cells, then the macrophages release collagen destroying enzymes (MMPs) and allow the tumour to spread and get new blood flow.

Immune stimulants like zinc are involved in breaking down our collagen, if someone has cancer and IDO is active and M2 macrophages are active then the zinc is like adding petrol to the site and can help the tumour to spread.
Zinc is best obtained from a good diet but may be needed in a supplement if a person has poor blood flow, fibrosis and needs the immune system to heat up.
Just some caution is needed with zinc and cancer.

“Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.”

Any means of lowering IDO can helps to flick the immune system back to the M1 macrophage mode and our white blood cells can then see our cancer cells, recognise them and remove them.

Aloe Vera, Myoga ginger and Papaya leaf tea are IDO inhibitors, green tea works. Broccoli, cauliflower and cabbage seem to be IDO inhibitors which flick the immune system in the right direction, this may be because all the cruciferous vegetables inhibit estrogen, and estrogen suppresses t-cells and raises IDO, all of them have anti-cancer properties regardless of IDO inhibition.

 “In this phytochemical study, 18 known compounds were isolated from aqueous dissolved Aloe exudates. All of the isolated compounds were examined for their ability to inhibit IDO activities for a series of anthraquinone derivatives isolated from the Aloe extract; the IC50values of these compounds ranged from 39.41 to 53.93 µM. Enzyme kinetic studies of their modes of inhibition indicated that all of the compounds were uncompetitive inhibitors.”
“The aqueous dissolved Aloe exudate can be used as a source of novel natural IDO inhibitors and merit testing as therapeutic agents in the treatments of cancer and immunopathologic diseases, such as autoimmune, inflammatory, and allergic disorders.”

“Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation.’
‘As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity.’
‘Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related disease.’

Papaya leaf tea flicks macrophages and t-cells towards an anti-tumour mode, papaya leaf also has proven anti-cancer effects with few side effects.

" University of Florida researcher Dr. Nam Dang, and colleagues in Japan have documented papaya’s dramatic anticancer effect against a broad range of lab-grown tumors, including cancers of the cervix, breast, liver, lung and pancreas. The researchers used an extract made from dried papaya leaves, and the anticancer effects were stronger when cells received larger doses of the tea.
In a paper published in the Feb. 17 issue of the Journal of Ethnopharmacology, Dang and his colleagues also documented for the first time that papaya leaf extract boosts the production of key signaling molecules called Th1-type cytokines. This regulation of the immune system, in addition to papaya’s direct antitumor effect on various cancers, suggests possible therapeutic strategies that use the immune system to fight cancers.
The papaya extract did not have any toxic effects on normal cells, avoiding a common and devastating consequence of many cancer therapy regimens.”

Foods that prevent the cell fusion of tumour cells are bromelain from pineapples, green tea, turmeric, olives and olive oil, black cumin. Preventing cell fusion is a way to stop tumour spread so these foods listed can be quite potent.
Bromelain and turmeric are strong blood thinners so not to be used with Warfarin or other blood thinning drugs and not near surgery.

Other foods that suppress tumours are sulphur and selenium foods like garlic and brazil nuts, resveratrol from grapes and berries, all purple foods like beetroot, pomegranates and berries, herbs like sage, thyme, rosemary and oregano, plus tomatoes, can you see the Mediterranean diet here?
This is the effect IDO has on T-cells which are like road markers for the macrophages to either come in and rip up the tarmac (damaged or infected areas) or come in and lay down concrete (collagen).
IDO flicks the Th1 t-cells off.

“In conclusion, IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote Fatty Acid synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages.”

It should be noted that white blood cells are as busy taking out old collagen and making new collagen in all diseases like heart disease, arthritis, osteoarthritis, Crohn’s disease, nerve diseases and so on.
The immune system is not there merely for infections and this myth needs to be flipped on its head, if you say are poisoning your body with sugar and alcohol then cells are dying so the immune system then must keep up with removing the debris that is clogging up arteries and organs.

The Catch 22 with inflammatory diseases like heart disease, arthritis and osteoarthritis, is the immune system is in the M1 macrophage mode with CD4 T-cells causing much of the inflammation and collagen breakdown as the immune system tries to dig out rubbish.
While the M2 macrophages can be causing bad fibrosis or clogging arteries.

The other aspect of Aloe Vera apart from being an IDO inhibitor is that mannose sugars seem to allow the white blood cells to attach to old collagen and remove it, so a deficiency in mannose sugars may cause fibrosis (too much collagen) and poor blood flow.
Aloe Vera or Mannose can tag damaged collagen for removal, but it stimulates the immune system so care needs to be taken with Aloe Vera use if there are any signs of autoimmune disease.
Mannose from Aloe Vera or the supplemental form seems to be necessary for preventing fibrosis which can occur in cancer, autoimmune diseases and diabetes but the D-Mannose supplement may be the safer form to use.

This fibrosis occurs in many diseases, so the concept is like this, long term inflammation causes lesions and wounds which the immune system tries to fix by plugging it up with collagen, this is fibrosis.
Examples of mannose, collagen repair and the M2 macrophage function are here.

 “We show that Mannose Receptor is able to bind and internalise collagen in a carbohydrateindependent manner and that Mannose Receptor deficient macrophages have a marked defect in collagen IV and gelatin internalisation.”

Successful tissue remodelling and maintaining body structure is an essential part of immunity.

“Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds”

“Morphogenesis, tissue remodeling, and tissue repair all require the targeted remodeling of interstitial and basement membrane collagen to allow for organ growth, cell migration, and translation of contextual cues that are embedded within the extracellular matrix. Perturbed collagen homeostasis underlies a remarkable array of important human diseases, including fibrosis, that are attributable to excess interstitial deposition of collagen and degenerative diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, which are characterized by a loss of collagen from tissues. Finally, the ability of tumor cells to leave their site of origin and seed at novel locations is dependent on their ability to orchestrate the local degradation of collagen”

To treat heart disease, arthritis and osteoarthritis you also need a lot of vitamin C for collagen repair or new collagen (lemons are excellent source of vitamin C for example as they reduce acidity and uric acid via potassium citrate).
Citrus like Grapefruit have Naringin which helps bone formation.
Uric acid also keeps our white blood cells or macrophages busy trying to remove the uric acid crystals so uric acid and gout drives us towards cancer with inflammation.
Celery is very useful if uric acid is high.
Lemons with orange juice or pineapple should be eaten before meals as they help digest food. Vitamin C is a basic, simple and cheap anti-inflammatory.

 “Inflammation is the physiological response of the body to harmful stimuli, such as injury, pathogens, damaged cells, or irritants. Inflammatory response can be either acute or chronic, which leads to pathology. The major function of innate immune cells is identification and recognition of the injurious and/or foreign substances causing the defense response. Macrophages are actively involved in all phases of inflammation, and their role as effector and regulatory cells is now widely recognized. Another interesting and important role of macrophages is their high level of specialization and tissue specificity. While all tissue-bound macrophages differentiate from circulating monocytes, they acquire distinct characteristics and functions locally due to their response profiles. One of the major factors for this diversity is the complexity of microbial load as well as tissue architecture.”

These studies below are all diseases where IDO activity rises as people get ill.


 “The patients who died had significantly higher concentrations of Kyn and significantly lower Tryptophan concentrations, resulting in significantly higher IDO activity”

“High IDO activity in winter predicted subsequent activation of SLE in spring and summer. Our results indicate that IDO-dependent immunosuppressive mechanisms are activated in SLE patients.”




Type 2 diabetes can be described as a disease where long term CD4 T-cell activity and white blood cells have caused massive inflammation leading to damage of pancreatic cells.
Towards the end stage of diabetes the immune system has flopped and people get gangrene and infections, this is where any IDO lowering can flick the immune system back on so people survive, of course vitamin C plus anti-inflammatory foods in the Mediterranean diet should have been used well before this end stage to lower inflammation and allow collagen repair.

“IDO activity increased with severity of chronic kidney disease”

HAART or anti-retroviral drugs for so called HIV/AIDS are mild IDO inhibitors which is why they partly work but the side effects make them an expensive and hit or miss therapy because they cause liver damage and lipodystrophy.
Antiretroviral drugs also cause inflammation which appears to be why ARV’s stimulate T-cells. High t-cells really can indicate a lot of repair is needed so interpreting high t-cells as being healthier is problematic unless too low.

“Among 76 participants, higher baseline IDO activity was associated with lower CD4+ T cell counts (P<0.05) and higher plasma sCD14 levels (P<0.001). After 1 year of HAART, IDO activity decreased significantly (P<0.01), but was still higher than in healthy controls (P<0.05). The baseline IDO activity did not predict CD4+ T cell recovery after 1 year of therapy. The percentages of myeloid and plasmacytoid dendritic cells were not correlated with IDO activity.
Conclusions
IDO activity is elevated in HIV-infected patients, which is partially associated with microbial translocation. HAART reduced, but did not normalize the activity of IDO.”


Vitamin B6 is an IDO inhibitor because it raises serotonin, our main anti-depressant which is created from tryptophan, when IDO levels rise tryptophan levels go lower because IDO is breaking it down and people can get depressed.
If people get depressed they chew through tryptophan and this also proves therapies like massage, meditation, watching comedies, doing art, playing music or moderate exercise like walking in the sun are literally antidepressants which can lower IDO and turn on your immune system.

Excessive exercise is counter-productive because it lowers tryptophan and can raise IDO, take note fitness junkies.

Cheese has a good amount of tryptophan, I use cheese as a source of tryptophan to help sleep at night. Anyone on a low protein diet is likely to have low tryptophan.
This is a basic list of tryptophan foods, “chocolate, oats, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, buckwheat, spirulina, and peanuts.”
Protein therefore can be part of anti-depressant therapy.

“The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression.”

All of the suggestions for lowering IDO and preventing cell fusion should enhance chemotherapy effect, Bromelain for instance is a chemo potentiator.

As a final point on how depression can trigger the IDO enzymes by depleting Tryptophan, the approach to giving a pessimistic diagnosis should be mentioned.
Voodoo and bone pointing curses are still a reality in our modern world because hi-tech testing machines that detect a ‘possible’ life threatening illness can have the same effect as bone pointing curses, we make patients depressed.
Knowing the effect and telling a patient can help their immunity.
For practitioners this means all types of therapy that help a better mood works, an example is a leftfield study like this, happiness is an IDO inhibitor.

“INTERVENTION: Viewing of a humor video for 1 hour. Blood samples were taken 10 minutes before, 30 minutes into, and 30 minutes and 12 hours after the intervention.”
“RESULTS: Increases were found in natural killer cell activity; immunoglobulins G, A, and M, with several immunoglobulin effects lasting 12 hours into recovery from initiation of the humor intervention; functional phenotypic markers for leukocyte subsets such as activated T cells, active cytotoxic T cells, natural killer cells, B cells, helper T cells, uncommitted T cells with helper and suppressor markers, helper/suppressor ratio with several leukocyte subset increase effects lasting 12 hours after the humor experience; the cytokine interferon-gamma, with increases lasting 12 hours; total leukocytes, with specific subpopulation lymphocytes during the intervention and 90 minutes into recovery; and granulocytes during the intervention and 90 minutes following the intervention”

For anyone interested this is a list of things that may help our macrophages to work properly, I’m still researching this subject.

Lupeol, Resveratrol, Geraniin, Aloe-emodin, Quercetin, Curcumin, Naringenin, Apigenin, Chrysin, Procyanidins, Epigallocatechin gallate, Berberine, Apocynin, Paeonol and Terpenes.

Hope this helps





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