Dr. Ayşegül Çoruhlu
What is ‘Cytokine Storm’?
Have you heard of dying from the virus in Covid19 disease? In other words, does the virus kill or does the fight against the virus kill?
In this article, we will learn that the disease tableau in Covid19 disease is not caused by the virus but by the defensive response to the virus. We will see that this defensive response varies from normal to ‘excessive’. We will examine the cause of this excess.
The excessive immune response to Covid is called the ‘cytokine storm’. I will mention one of the possible causes explaining the excessive macrophage response of ‘macrophage activation syndrome’.
So that means macrophages are effective in the response to Covid. In that case, let’s get to know them.
Macrophages are divisions in the defense system. The duty is in the name; to destroy the enemy by ‘eating’ them (phage = to eat). In Covid our topic is macrophages in the alveoli of the lungs, because they are among the first to fight the virus.
Macrophages form from a preliminary material called monocyte. There are two basic types; M1 macrophages and M2 macrophages.
Differentiating these two is very, very, very important. Because the severity of Covid is determined by which of these is more active than the other. Let’s explain from beginning to end. If M1 is active, we’re in trouble. If M2 is active, we may recover more easily but problems may occur while healing. We will easily overcome the disease if the M1/M2 ratio is ideal.
How do macrophages create this difference?
Macrophage polarization: selection of macrophages
Based on stimuli, macrophages determine whether M1 or M2 will be present. If the external stimulant is a virus, macrophages evolve toward M1. Why?
M1 macrophages are activated when the virus enters cells. Their job is to destroy the virus.
The order given to M1 macrophage is ‘KILL’. M1s are destructive macrophages. They are deadly. Let’s list their features:
1. They work as antivirals
2. They kill agents in cells
3. They cause inflammation
4. They release inflammatory cytokines
5. They are involved in interferon release (interferon is the body’s antiviral cytokine)
6. They use free radicals inducing oxidation to kill
7. If M1 works too much, these free radicals they produce damage tissue.
M1s kill viruses but the bill for this killing is paid for by tissues, just like in war., All tissues where the disease is present are damaged, led by the lungs
Let’s look more closely at this price of killing of tissue damage.
M1 macrophages have very sharp virus-killing weapons available. They have very different weapons. The first important weapon is NO, nitric oxide.
NO, Nitric Oxide
Arginin —> INOS enzyme —-> NO + citrulline
NO later combines with other free radicals to produce a strong free radical called peroxynitrite. In other words, NO is a weapon. Apart from NO, free radicals called ROS are produced from oxygen.
Another important point: M1 macrophages produce free radicals from iron. I’ll come to that topic later.
Activation of M1 macrophages ensures activation of the Th1 group from T lymphocytes. Th1 lymphocytes and M1 macrophages work together. Th1 activation is one of the first systems occurring in the war with the virus. They organize the direct war with the virus. When Th1s and M1s finish killing the virus together, the number 2s of these systems come into play. In other words, M2 macrophages and Th2 lymphocytes. Let’s see what they do.
For M1 macrophages the order is ‘KILL’. For M2 macrophages the order is ‘HEAL’. M2s clean the battlefield and ensure healing. They ameliorate damage in tissues. Let’s list the properties of M2.
1. They have no interest in killing the virus
2. They don’t kill anyone
3. They reduce inflammation
4. They calm the cytokine storm
5. They produce anti-inflammatory matter like IL-10
6. They use arginine, which M1s use to make free radicals, as a building block, and heal tissue
7. With arginine —->arginase enzyme = Ornithine+ urea + building blocks, they heal tissue
8. If they work too much, they may cause excess tissue formation and fibrosis
9. They work with Th2 lymphocytes. Th2 lymphocytes are lymphocytes related to creating immunity and antibodies.
Up to this point, we understand that M1 kills the virus and after M1s job is done, we need to transition to M2.
In Covid19, the cytotoxic effect linked to M1 activation is very high. The cytokine called interleukin 6 increases a lot linked to this activation. The CRP blood value, showing inflammation, is high. Another notable high blood value in Covid19 is FERRITIN. In fact, ferritin elevation is in parallel with poor prognosis for the disease. As it gets higher, the disease progression becomes that much worse. Let’s look at why ferritin increases.
High Ferritin and COVID-19
Ferritin is the stored form of iron. Generally, it increases in most diseases that involve high inflammation. That’s how it is here. However, I want to state that my own opinion is that the very high ferritin in Covid19 is again related to excessive M1 macrophage activation. M1 macrophages ‘hold’ iron.
In the body, 80% of iron is within erythrocytes. The hemoglobin in erythrocytes is in the form of HEM. Normally aging erythrocytes are eaten by macrophages and the iron they contain is returned to the cycle. In infectious situations, there is more HEM destruction and separation of the iron it contains. There are two targets with this. The first is that with the separation of iron from Hem, the iron can combine with hydrogen peroxide to form a new weapon. This is called the Fenton reaction.
Hem ——> Hem oxygenase 1 (HO-1) enzyme = CO (carbon monoxide)+iron+ biliverdin (then bilirubin)
In this way, iron is separated. Here the iron combines with hydrogen peroxide to form a type of free radical. This then battles with the virus.
The second aim is as follows: microorganisms require iron. They need iron for proliferation in order to make DNA, or in the case of SARScov2 RNA. There are many studies about bacteria in relation to this topic, but very few written about the iron requirements of viruses. I think we are missing information about this topic. The electron donor of iron is required for life by all organisms. Among studies about the HIV virus, there are publications stating that the use of desferrioxamine, which causes iron chelation, reduces the proliferation rate of the HIV virus. We know that ferritin increases excessively in Covid19 disease. Because M1 macrophages store the iron from hem occurring by degradation of erythrocytes as ferritin. But I have not encountered anything about iron chelation.
Again, let’s look at the differences between M1 and M2 macrophages in terms of iron:
· M1s have high HO-1 enzyme (enzyme destroying hem) activity
· M2s don’t have this enzyme.
· M1s store iron, ferritin showing stored iron increases as a result
· M2s release iron lowering ferritin
· M1s may cause anemia
· M2s do not.
For viral infections like Covid19, it is important to ‘rapidly kill’ the enemy. Because defense needs to be more rapid than proliferation of the virus. Viruses can rapidly proliferate within hours, and SarsCov2 is a rapidly proliferating virus. M1 macrophages fight against this rapid proliferation. However, after M1s, M2s need to calmly enter the cycle to improve the environment. It appears that this does not happen or happens late in Covid19.
In those with Covid19, our bodies meet this virus for the first time and attempt to overcome this rapidly-proliferating virus. In disease, M1s are very active, we see they may harm the body with the cytokine storm and IL-6, CRP and ferritin elevation are the results of this activation.
In the body, the button for turning on M1 and M2 macrophages is determined by the redox state of tissues. In other words, if reduction is dominant in alveoli instead of oxidation, things may progress more easily. We said that oxidation is caused by M1-mediated free oxygen and nitrogen radicals.
Contrary to this, reduction is determined by the glutathione amount in alveoli. Here, administering acetyl cysteine as inhalation agent or by IV may be recalled (acetyl cysteine is a precursor of glutathione).
In summary of the situation, we said M1 activation was stronger than needed. However, are M1 macrophages only increased by viruses?
No. The greatest increase is by LPS.
LPS means membranes of bad bacteria in our intestines. Membranes mean gram negative bacteria.
· If there is leaky gut
· If processed products containing gluten, flour and sugar are eaten
· If the diet is not plant dominant
· If it is not well-chewed
· If fiber is not consumed, the intestinal is damaged and leaky gut is possible
· LPS entering the blood through these gaps cause very very severe activation of M1s
There are studies about the severity of Covid19 disease and intestinal health. The majority of those with severe disease have intestinal problems. Preventing LPS relatively reduces the excessive M1 macrophage response. Perhaps with this aim, consumption of
· Intestinal enzymes
can be recommended.
Another topic that activates M1 macrophages is diabetes and obesity. Blood sugar regulation and weight loss should be remembered.
To reduce tissue damage following excessive activation of M1 and Th1, the correct approach is to try to reduce the harm caused to us by free radicals, a weapon used against the virus. M1 activity occurs most through free radicals called NOS, linked to NO. Food and supplements containing sulfur are important to neutralize these. In this way, the thiol pool should be supported.
All types of plants (especially purple ones) are supports for free radicals forming from oxygen (ROS). Whether sulfur or polyphenols in plants, the sought-after feature is supports that donate electrons. The most basic electron donors are foods containing vitamin C. It’s important not to write again all the names of vitamins and nutrients which are important for immunity.
It may be interesting to you: in allergy and asthma patients, M2 activity is high not M1. Some statistics state that the disease progresses more slowly in these people.
The aim of this article is to answer the question of ‘why does the immune system overreact and what does it mean’ and to question whether excessive activation of M1 alveolar macrophages fighting the virus on the front lines should be a topic of investigation or not. In my first article at the start of March I said ‘excess Th1 activity forms a problem’ and this continues that thread. Th1 and M1 work together.
This article may help us to understand ferritin elevation in covid19 disease.
With love and respect,