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Macrophage Polarization and IDO Enzymes, Immunity, Cancer and Depression

by Cal (Gerard) Crilly(more info)

listed in immune function, originally published in issue 293 - March 2024


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 or foetal cells [1], stem cells [2] or any new cells to tell the M1 macrophages to avoid any area of growth and repair and not gobble it up. Hence cancer cells [3] releasing IDO can avoid our own immune system and stay alive.



Different stimuli, surface markers, secreted cytokines, and biological functions
between M1 and M2 macrophages

Credit: Yongli Yao, Xiang-Hong Xu, Liping Jin  on Wikipedia


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 main functions, one is collagen deposition, while the other function is to dig out large scale infections [4] 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 [4]. They also work with other immune cells to deposit collagen for repairing damaged areas [5] 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 [6], the white blood cells use our own retroviruses to fuse together [7] into the giant multinucleated cells.

In the last decade retroviruses have been found to fuse sperm [8] and eggs [9], they are needed in pregnancy [10], are used fuse osteoclasts [11] to remove bone, and fuse muscles [12] together so our retroviruses have function in immune activity and structure.

When cancer occurs the tumours release IDO [13] 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 [14], then the macrophages release collagen destroying enzymes (MMPs) [15] and allow the tumour to spread and get new blood flow.

Immune stimulants like zinc are involved in breaking down our collagen [16], if someone has cancer and IDO is active [17] 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.

“Tumour 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 tumours. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.”

Targeting the indoleamine 2,3-dioxygenase pathway in cancer [18]

Ways to Lower IDO Enzymes

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 [19] are IDO inhibitors, green tea [20] works. Broccoli, cauliflower and cabbage seem to be IDO inhibitors which also prevent t-cell autoimmunity. The IDO inhibition may be because all the cruciferous vegetables inhibit estrogen, and estrogen suppresses t-cells and raises IDO [21].

“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.”

Chemical Components from Aloe and their Inhibition of Indoleamine 2, 3-dioxygenase [22]

“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 tumours, 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.”

Effects of various phytochemicals on indoleamine 2,3-dioxygenase 1 activity: galanal is a novel, competitive inhibitor of the enzyme [23]

Papaya leaf tea or extract diverts macrophages and t-cells towards an anti-tumour mode, papaya leaf has proven anti-cancer effects with few side effects. Papaya leaf also can increase platelets [24] to prevent bleeding problems.

“The leaves of Carica papaya have been used as remedy for various disorders, including cancer.

In this paper, we demonstrate that the aqueous-extracted fraction of Carica papaya leaf has several in vitro biological effects: (1) anti-proliferative effect on tumour cells; (2) promotion of Th1 type cytokine production; (3) enhancement of cytotoxicity against tumour cells; (4) upregulation of anti-tumor related genes on PBMC; and (5) the active components of Carica papaya extract to be the fraction with MW. less than 1000.

These findings are the first report that demonstrated anti-tumour effect of the leaves of Carica papaya, and suggested possibility of inducing a shift to Th1 type immune responses.’

Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects [25]

Foods that prevent the cell fusion [26] of tumour cells and macrophages [27] are bromelain [28] from pineapples [29], green tea [30], turmeric [31] or curcumin [32], and black cumin [33].

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 or after surgery.

Other foods that suppress tumours are selenium foods like brazil nuts [34], only 2 or 3 a day to be safe. Sulphur foods like broccoli and garlic [35], olives [36] and olive oil, resveratrol [37] from grapes [38] and berries, all purple foods [39] like beetroot [40], pomegranates [41] and berries, herbs like sage [42], thyme [43], rosemary [44], oregano [45], plus tomatoes [46], can you see the Mediterranean diet here?

Vitamin B3 or Nicotinamide may be one of the most important IDO lowering vitamins.

Summarised below, IDO may be breaking down tryptophan to use for Nicotinamide synthesis used in the NAD+ energy needs of cells.

“A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3‐dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD+ supplies. We hypothesize that an insufficient cellular NAD+ supply is the root cause of metabolic shifts in macrophages. We assert that manipulation of nicotinamide pathways may correct deleterious immune responses. We propose evaluation of nicotinamide (Vitamin B3) and analogues, including isoniazid, nicotinamide mononucleotide and nicotinamide riboside, as potential therapy for infectious causes of sepsis, including COVID‐19.”

Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts [47]

Vitamin B6 [48] is also an IDO inhibitor [49] because it is need to make tryptophan and serotonin.

If people get depressed they chew through tryptophan [50], this indicates that therapies like massage, meditation, watching comedies [51], doing art, playing music or moderate exercise are physical and psychological antidepressants which could lower IDO and turn on your immune system. Excessive exercise [52] 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, yoghurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, buckwheat, spirulina, and peanuts.”

Protein therefore should be part of anti-depressant/immune boosting 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.”

A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase [53]

The basic dose a day is around 500mg of B3 and 100mg of B6 for adults with adequate protein containing tryptophan to lower IDO and reduce depression.

‘Trytophan, vitamin B6, and nicotinamide-containing supplements loading between meals can quickly improve depressed mood in quite low dose in young adults with severe subclinical depression.’ [54]

IDO Enzymes, Macrophages and Fibrosis

Below 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).

If the collagen or tarmac is damaged or too old then this gets called fibrosis and becomes a problem.

A good example is pulmonary fibrosis or COPD where the collagen deposits in the lungs as scarring tissue and block breathing.

Too much IDO flicks Th1 t-cells off so they fail to remove bad collagen.

“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.” [55]

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, if you are poisoning your body with too much sugar and alcohol then cells are dying so the immune system then must also 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 that the immune system is in the inflammatory M1 macrophage mode with CD4 T-cells causing much of the inflammation [56] and collagen breakdown [57] as the immune system tries to dig out rubbish.

While the M2 macrophages can be causing bad fibrosis [58] or clogging arteries [59].

The other aspect of Aloe Vera apart from being an IDO inhibitor is that its mannose sugars seem to allow the white blood cells to attach to old collagen [60] 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.

Short examples and explanations of mannose, collagen repair and the M2 macrophage function are below.

“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 gelatine internalisation.”

Carbohydrate‐independent recognition of collagens by the macrophage mannose receptor [61]

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

“Tissue remodelling processes critically depend on the timely removal and remodelling of pre-existing collagen scaffolds”

“Morphogenesis, tissue remodelling, and tissue repair all require the targeted remodelling 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 tumour cells to leave their site of origin and seed at novel locations is dependent on their ability to orchestrate the local degradation of collagen”

M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway [60]

To treat heart disease, arthritis and osteoarthritis you also need a lot of vitamin C for white blood cells [62] or new collagen [63] (lemons are excellent source of vitamin C for example as they reduce acidity and uric acid [64] via potassium citrate [65].

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 [66] and gout drives us towards cancer with inflammation.

Celery is also 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 [62].

“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 defence 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.”

Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases [67]

In Conclusion

These are some diseases where IDO activity may rise as people get ill.

Sepsis [47], bacterial infections [68], pneumonia [69], tuberculosis [70], influenza [71], systemic lupus erythematosus or SLE [72], Epstein-Barr and cancer [73], liver diseases and fibrosis [74], HIV [75] and COVID-19 [76].

This review explains the effect of IDO on t-cells and immunity, well worth checking.

Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux? [77]

As a final point on how depression could trigger the IDO enzymes by depleting Tryptophan, the approach to how we give 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 can make patients depressed and ill.

Knowing the effect and telling a patient about the effect can help their immunity.

For practitioners this means all types of therapy that help a better mood works, an example is a left field study like this, happiness is possibly an IDO inhibitor.

Intervention: Viewing of a humour 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 humour 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 humour 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”

Modulation of neuroimmune parameters during the eustress of humor-associated mirthful laughter [78]

For anyone interested this is a list of things to look at 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.

Phytochemicals as modulators of M1-M2 macrophages in inflammation [79]

Quinones, Polyphenols and Alkaloids

Indoleamine 2, 3-dioxygenase 1 inhibitory compounds from natural sources [80]


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About Cal (Gerard) Crilly

Cal (Gerard) Crilly is a self-taught researcher from Brisbane, Australia.

He has been a registered nutritionist in Australia from 2017 to 2022 and now works as a health care worker in the UK.

Cal is 59 and has played in various Australian bands for 40 years and has a large film archive of Brisbane bands on YouTube.

School education was in England and Ireland. He may be contacted via

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