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 carbohydrate‐independent 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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