MACROPHAGES. Macrophage (from ancient Greek, large eater) are a special type of large white blood cells, which, simultaneously with those cells that, in fact, are their predecessors, create a symbiosis called the system of mononuclear phagocytes (from ancient Greek, “to absorb (eat) cell"). In this case, monoblasts, promocytes and monocytes act as precursor cells.

Origin and purpose of macrophages

Macrophages are called “scavenger” cells for a reason, since everything they come into contact with is absorbed and destroyed through digestion. A certain proportion of macrophages are constantly located in certain places: in capillaries and lymph nodes, in the liver, in the lungs, in connective and nervous tissues, in bones, including bone marrow. Others wander between cells, gradually accumulating in those places where one or another infectious agent is most likely to enter the body.
All types of macrophages originate from blood monocytes, and monocytes, in turn, arise from bone marrow promonocytes, which gradually mature from earlier progenitor cells until a certain stage is reached. Notably, macrophages have a feedback loop with these progenitor cells; provided due to their ability to produce cytokines (growth factors) into the blood, which enter the bone marrow with the blood, thereby enhancing the natural processes of cell division that were formed earlier. This process is activated, for example, in the presence of certain infections, when many macrophages die in the fight against “enemies”, they are replaced by new macrophages, maturing at an accelerated pace in the bone marrow.

How do macrophages “work” in the presence of infections in the body?

GcMAF is a unique drug for activating the activity of macrophages

Unfortunately for us, despite their enormous capabilities, macrophages may be inactive. For example, all cancer cells, as well as viral and infectious cells, produce the protein alpha-N-acetylgalactosaminidase (nagalase), which blocks the production of GcMAF glycoprotein, which stimulates the activation of macrophages, thus interfering with the normal functioning of the immune system. And in the absence of immune system activity, malignant tumors develop uncontrollably and the level of viral infections increases. In this case, there is a drug called GcMAF, which activates macrophages and enhances the activity of the immune response. You can purchase genuine GcMAF at Dr. Vedov’s clinic.

Macrophage is multifaceted and ubiquitous

One hundred and thirty years ago, the wonderful Russian researcher I.I. Mechnikov, in experiments on starfish larvae from the Strait of Messina, made an amazing discovery that radically changed not only the life of the future Nobel laureate, but also turned upside down the then ideas about the immune system.

Sticking a pink thorn into the transparent body of the larva, the scientist discovered that the splinter was surrounded and attacked by large amoeboid cells. And if the foreign body was small, these wandering cells, which Mechnikov called phagocytes (from the Greek devourer), could completely absorb the alien.

For many years it was believed that phagocytes perform the functions of “quick reaction troops” in the body. However, recent studies have shown that, due to their enormous functional plasticity, these cells also “determine the weather” of many metabolic, immunological and inflammatory processes, both normally and in pathology. This makes phagocytes a promising target when developing strategies for treating a number of serious human diseases.

Depending on their microenvironment, tissue macrophages can perform various specialized functions. For example, macrophages of bone tissue - osteoclasts, also remove calcium hydroxyapatite from bone. If this function is insufficient, marble disease develops - the bone becomes overly compacted and at the same time fragile.

But perhaps the most surprising property of macrophages turned out to be their enormous plasticity, i.e., the ability to change their transcriptional program (“turning on” certain genes) and their appearance (phenotype). The consequence of this feature is the high heterogeneity of the cell population of macrophages, among which there are not only “aggressive” cells that defend the host organism; but also cells with a “polar” function, responsible for the processes of “peaceful” restoration of damaged tissues.

Lipid "antennas"

The macrophage owes its potential “many faces” to the unusual organization of genetic material – the so-called open chromatin. This incompletely studied variant of the cellular genome structure ensures rapid changes in the level of gene expression (activity) in response to various stimuli.

The performance of a particular function by a macrophage depends on the nature of the stimuli it receives. If the stimulus is recognized as “foreign,” then activation occurs of those genes (and, accordingly, functions) of the macrophage that are aimed at destroying the “alien.” However, the macrophage can also be activated by signaling molecules of the body itself, which induce this immune cell to participate in the organization and regulation of metabolism. Thus, in “peacetime” conditions, i.e. in the absence of a pathogen and the inflammatory process caused by it, macrophages participate in the regulation of the expression of genes responsible for the metabolism of lipids and glucose, and the differentiation of adipose tissue cells.

Integration between the mutually exclusive “peaceful” and “military” directions of macrophage work is carried out by changing the activity of receptors in the cell nucleus, which are a special group of regulatory proteins.

Among these nuclear receptors, special mention should be made of the so-called lipid sensors, i.e. proteins capable of interacting with lipids (for example, oxidized fatty acids or cholesterol derivatives) (Smirnov, 2009). Disruption of these lipid-sensing regulatory proteins in macrophages may cause systemic metabolic disorders. For example, a deficiency in macrophages of one of these nuclear receptors, designated PPAR-gamma, leads to the development of type 2 diabetes and an imbalance of lipid and carbohydrate metabolism throughout the body.

Cellular metamorphoses

In the heterogeneous community of macrophages, based on the basic characteristics that determine their fundamental functions, three main cellular subpopulations are distinguished: macrophages M1, M2 and Mox, which are involved, respectively, in the processes of inflammation, repair of damaged tissue, and protection of the body from oxidative stress.

The “classical” M1 macrophage is formed from a precursor cell (monocyte) under the influence of a cascade of intracellular signals that are triggered after recognition of an infectious agent using special receptors located on the cell surface.

The formation of the M1 “eater” occurs as a result of powerful activation of the genome, accompanied by activation of the synthesis of more than a hundred proteins - the so-called inflammatory factors. These include enzymes that promote the generation of oxygen free radicals; proteins that attract other cells of the immune system to the site of inflammation, as well as proteins that can destroy the bacterial membrane; inflammatory cytokines are substances that have the properties of activating immune cells and having a toxic effect on the rest of the cellular environment. Phagocytosis is activated in the cell and the macrophage begins to actively destroy and digest everything that comes in its way (Shvarts, Svistelnik, 2012). This is how a focus of inflammation appears.

However, already at the initial stages of the inflammatory process, the M1 macrophage begins to actively secrete anti-inflammatory substances - low molecular weight lipid molecules. These “second-tier” signals begin to activate the above-mentioned lipid sensors in new “recruits” monocytes arriving at the site of inflammation. A chain of events is triggered inside the cell, as a result of which an activating signal is sent to certain regulatory sections of DNA, enhancing the expression of genes responsible for harmonizing metabolism and simultaneously suppressing the activity of “pro-inflammatory” (i.e., provoking inflammation) genes (Dushkin, 2012).

Thus, as a result of alternative activation, M2 macrophages are formed, which complete the inflammatory process and promote tissue repair. The M2 macrophage population can, in turn, be divided into groups depending on their specialization: dead cell scavengers; cells involved in the acquired immune response, as well as macrophages, secreting factors that contribute to the replacement of dead tissue with connective tissue.

Another group of macrophages, Moss, is formed under conditions of so-called oxidative stress, when the danger of damage to tissues by free radicals increases. For example, Moss constitute about a third of all macrophages in an atherosclerotic plaque. These immune cells are not only resistant to damaging factors themselves, but also participate in the body's antioxidant defense (Gui et al., 2012).

Foamy kamikaze

One of the most intriguing metamorphoses of a macrophage is its transformation into a so-called foam cell. Such cells were found in atherosclerotic plaques, and got their name because of their specific appearance: under a microscope they resembled soap foam. In essence, a foam cell is the same M1 macrophage, but overflowing with fatty inclusions, mainly consisting of water-insoluble compounds of cholesterol and fatty acids.

A hypothesis was put forward, which has become generally accepted, that foam cells are formed in the wall of atherosclerotic vessels as a result of the uncontrolled absorption of low-density lipoproteins by macrophages, which carry “bad” cholesterol. However, it was subsequently discovered that the accumulation of lipids and a dramatic (tens of times!) increase in the rate of synthesis of a number of lipids in macrophages can be experimentally provoked by inflammation alone, without any participation of low-density lipoproteins (Dushkin, 2012).

This assumption was confirmed by clinical observations: it turned out that the transformation of macrophages into foam cells occurs in various diseases of an inflammatory nature: in joints - with rheumatoid arthritis, in adipose tissue - with diabetes, in kidneys - with acute and chronic failure, in brain tissue - with encephalitis . However, it took about twenty years of research to understand how and why a macrophage during inflammation turns into a cell stuffed with lipids.

It turned out that activation of pro-inflammatory signaling pathways in M1 macrophages leads to the “switching off” of those same lipid sensors that under normal conditions control and normalize lipid metabolism (Dushkin, 2012). When they are “turned off,” the cell begins to accumulate lipids. At the same time, the resulting lipid inclusions are not at all passive fat reservoirs: the lipids included in their composition have the ability to enhance inflammatory signaling cascades. The main goal of all these dramatic changes is to activate and strengthen the protective function of the macrophage by any means, aimed at destroying “strangers” (Melo, Drorak, 2012).

However, high levels of cholesterol and fatty acids come at a cost to the foam cell - they stimulate its death through apoptosis, programmed cell death. On the outer surface of the membrane of such “doomed” cells, the phospholipid phosphatidylserine is found, which is normally located inside the cell: its appearance outside is a kind of “death knell”. This is the “eat me” signal that M2 macrophages perceive. By absorbing apoptotic foam cells, they begin to actively secrete mediators of the final, restorative stage of inflammation.

Pharmacological target

Inflammation as a typical pathological process and the key participation of macrophages in it is, to one degree or another, an important component primarily of infectious diseases caused by various pathological agents, from protozoa and bacteria to viruses: chlamydial infections, tuberculosis, leishmaniasis, trypanosomiasis, etc. At the same time, macrophages, as mentioned above, play an important, if not leading, role in the development of so-called metabolic diseases: atherosclerosis (the main culprit of cardiovascular diseases), diabetes, neurodegenerative diseases of the brain (Alzheimer’s and Parkinson’s disease, consequences of strokes and cranial -brain injuries), rheumatoid arthritis, and cancer.

Modern knowledge about the role of lipid sensors in the formation of various macrophage phenotypes has made it possible to develop a strategy for controlling these cells in various diseases.

Thus, it turned out that in the process of evolution, chlamydia and tuberculosis bacilli learned to use lipid sensors of macrophages in order to stimulate an alternative (in M2) activation of macrophages that is not dangerous for them. Thanks to this, the tuberculosis bacterium absorbed by the macrophage can, swimming like cheese in butter in lipid inclusions, calmly wait for its release, and after the death of the macrophage, multiply, using the contents of the dead cells as food (Melo, Drorak, 2012).

If in this case we use synthetic activators of lipid sensors, which prevent the formation of fatty inclusions and, accordingly, prevent the “foamy” transformation of the macrophage, then it is possible to suppress the growth and reduce the viability of infectious pathogens. At least in animal experiments, it has already been possible to significantly reduce the contamination of the lungs of mice with tubercle bacilli using a stimulator of one of the lipid sensors or an inhibitor of fatty acid synthesis (Lugo-Villarino et al., 2012).

Another example is diseases such as myocardial infarction, stroke and gangrene of the lower extremities, the most dangerous complications of atherosclerosis, which are caused by the rupture of so-called unstable atherosclerotic plaques, accompanied by the immediate formation of a blood clot and blockage of a blood vessel.

The formation of such unstable atherosclerotic plaques is facilitated by the M1 macrophage/foam cell, which produces enzymes that dissolve the collagen coating of the plaque. In this case, the most effective treatment strategy is to transform the unstable plaque into a stable, collagen-rich one, which requires transforming the “aggressive” M1 macrophage into the “pacified” M2.

Experimental data indicate that such a modification of the macrophage can be achieved by suppressing the production of pro-inflammatory factors in it. Such properties are possessed by a number of synthetic activators of lipid sensors, as well as natural substances, for example, curcumin, a bioflavonoid found in the root of turmeric, a well-known Indian spice.

It should be added that such transformation of macrophages is relevant for obesity and type 2 diabetes (most macrophages in adipose tissue have an M1 phenotype), as well as in the treatment of neurodegenerative brain diseases. In the latter case, “classical” activation of macrophages occurs in brain tissue, which leads to neuronal damage and the accumulation of toxic substances. The transformation of M1 aggressors into peaceful M2 and Mox janitors that destroy biological “garbage” may soon become the leading strategy for the treatment of these diseases (Walace, 2012).

Cancerous degeneration of cells is inextricably linked with inflammation: for example, there is every reason to believe that 90% of tumors in the human liver arise as a consequence of infectious and toxic hepatitis. Therefore, in order to prevent cancer, it is necessary to control the M1 macrophage population.

However, not all so simple. Thus, in an already formed tumor, macrophages predominantly acquire signs of M2 status, which promotes the survival, reproduction and spread of the cancer cells themselves. Moreover, such macrophages begin to suppress the anti-cancer immune response of lymphocytes. Therefore, for the treatment of already formed tumors, another strategy is being developed, based on stimulating signs of classical M1 activation in macrophages (Solinas et al., 2009).

An example of this approach is the technology developed at the Novosibirsk Institute of Clinical Immunology of the Siberian Branch of the Russian Academy of Medical Sciences, in which macrophages obtained from the blood of cancer patients are cultured in the presence of the stimulant zymosan, which accumulates in the cells. Macrophages are then injected into the tumor, where zymosan is released and begins to stimulate the classical activation of “tumor” macrophages.

Today it is becoming increasingly clear that compounds that induce metamorphosis of macrophages have a pronounced atheroprotective, antidiabetic, neuroprotective effect, and also protect tissues in autoimmune diseases and rheumatoid arthritis. However, such drugs currently available in the arsenal of a practicing physician—fibrates and thiazolidone derivatives—although they reduce mortality in these serious diseases, they also have severe side effects.

These circumstances stimulate chemists and pharmacologists to create safe and effective analogues. Abroad, in the USA, China, Switzerland and Israel, expensive clinical trials of similar compounds of synthetic and natural origin are already being conducted. Despite financial difficulties, Russian, including Novosibirsk, researchers are also making their contribution to solving this problem.

Thus, at the Department of Chemistry of Novosibirsk State University, a safe compound TS-13 was obtained, which stimulates the formation of Mox phagocytes, which has a pronounced anti-inflammatory effect and has a neuroprotective effect in an experimental model of Parkinson’s disease (Dyubchenko et al., 2006; Zenkov et al., 2009) .

At the Novosibirsk Institute of Organic Chemistry named after. N. N. Vorozhtsov SB RAS has created safe antidiabetic and antiatherosclerotic drugs that act on several factors at once, thanks to which the “aggressive” M1 macrophage turns into the “peaceful” M2 (Dikalov et al., 2011). Herbal preparations obtained from grapes, blueberries and other plants using mechanochemical technology developed at the Institute of Solid State Chemistry and Mechanochemistry of the SB RAS are also of great interest (Dushkin, 2010).

With the help of financial support from the state, it is possible in the very near future to create domestic means for pharmacological and genetic manipulations of macrophages, thanks to which there will be a real opportunity to transform these immune cells from aggressive enemies into friends who help the body maintain or restore health.

Literature

Dushkin M. I. Macrophage/foam cell as an attribute of inflammation: mechanisms of formation and functional role // Biochemistry, 2012. T. 77. P. 419-432.

Smirnov A.N. Lipid signaling in the context of atherogenesis // Biochemistry. 2010. T. 75. pp. 899-919.

Schwartz Ya. Sh., Svistelnik A. V. Functional phenotypes of macrophages and the concept of M1-M2 polarization. Part 1 Pro-inflammatory phenotype. // Biochemistry. 2012. T. 77. pp. 312-329.

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The main role in the development and maintenance of chronic inflammation belongs to the system of phagocytic macrophages (this concept replaced the previously widely used, but essentially insufficiently substantiated, term “reticuloendothelial system”). The main cell of this system is a macrophage, which developed from a blood monocyte. Monocytes, derived from bone marrow stem cells, first enter the peripheral blood, and from there into tissues, where, under the influence of various local stimuli, they transform into macrophages.

The latter are extremely important in the implementation of adaptive reactions of the body - immune, inflammatory and reparative. Participation in such reactions is facilitated by such biological properties of macrophages as the ability to migrate to foci of inflammation, the possibility of a rapid and persistent increase in cell production by the bone marrow, active phagocytosis of foreign material with rapid breakdown of the latter, activation under the influence of foreign stimuli, secretion of a number of biologically active substances, the ability to “ process” the antigen that has entered the body with subsequent induction of the immune process.

It is also fundamentally important that macrophages are long-lived cells that can function for a long time in inflamed tissues. It is important that they are able to proliferate in areas of inflammation; in this case, transformation of macrophages into epithelioid and giant multinucleated cells is possible.

Lacking immunological specificity (like T and B lymphocytes), the macrophage acts as a nonspecific auxiliary cell with the unique ability not only to capture the antigen, but also to process it so that subsequent recognition of this antigen by lymphocytes is greatly facilitated. This stage is especially necessary for the activation of T-lymphocytes (for the development of delayed-type immune reactions and for the production of antibodies to thymus-dependent antigens).

In addition to participating in immune reactions due to the pre-processing of the antigen and its subsequent “presentation” to lymphocytes, macrophages perform protective functions more directly, destroying some microorganisms, fungi and tumor cells.

Thus, in rheumatic diseases, not only specifically immunized lymphocytes, but also monocytes and macrophages that do not have immunological specificity, participate in the cellular reactions of immune inflammation.

These cells are attracted by monocyte chemotactic substances produced in areas of inflammation. These include C5a, partially denatured proteins, kallikrein, plasminogen activator, the main proteins from the lysosomes of neutrophils. T lymphocytes produce a similar factor upon contact with its specific antigen, B lymphocytes - with immune complexes.

In addition, lymphocytes also produce factors that inhibit the migration of macrophages (i.e., fixing them at the site of inflammation) and activating their function. In inflammatory foci, in contrast to normal conditions, mitoses of macrophages are observed and thus the number of these cells also increases due to local proliferation.

The importance of macrophages in maintaining the inflammatory process is determined by the anti-inflammatory agents released from these cells, discussed below.

1. Prostaglandins.

2. Lysosomal enzymes (in particular, during phagocytosis of antigen-antibody complexes, and the cell is not destroyed during their release).

3. Neutral proteases (plasminogen activator, collagenase, elastase). Normally, their quantity is negligible, but with foreign stimulation (phagocytosis), the production of these enzymes is induced and they are released in significant quantities. The production of neutral proteases is inhibited by protein synthesis inhibitors, including glucocorticosteroids. The production of plasminogen activator and collagenase is also stimulated by factors secreted by activated lymphocytes.

4. Phospholipase Az, which releases arachidonic acid from more complex complexes - the main precursor of prostaglandins. The activity of this enzyme is inhibited by glucocorticosteroids.

5. A factor that stimulates the release from bones of both mineral salts and the organic basis of the bone matrix. This factor exerts its influence on bone tissue through direct action, without requiring the presence of osteoclasts.

6. A number of complement components that are actively synthesized and secreted by macrophages: C3, C4, C2 and, apparently, also C1 and factor B, which is necessary for the alternative pathway of complement activation. The synthesis of these components increases when macrophages are activated and is inhibited by protein synthesis inhibitors.

7. Interleukin-1, which is a typical representative of cytokines - biologically active substances of a polypeptide nature produced by cells (primarily cells of the immune system). Depending on the sources of production of these substances (lymphocytes or monocytes), the terms “lymphokines” and “monokines” are often used. The name "interleukin" with its corresponding number is used to designate specific cytokines - especially those that mediate cell communication. It is not yet entirely clear whether interleukin-1, which is the most important monokine, represents a single substance or a family of polypeptides with very similar properties.

These properties include the following:

stimulation of B cells, accelerating their transformation into plasma cells;
stimulation of the activity of fibroblasts and synoviocytes with increased production of prostaglandins and collagenase;
pyrogenic effect, realized in the development of fever;
activation of the synthesis of acute-phase proteins in the liver, in particular the serum amyloid precursor (this effect may be indirect - due to stimulation of the production of interleukin-6).

Among the systemic effects of interleukin-1, in addition to fever, neutrophilia and proteolysis of skeletal muscles can also be noted.

8. Interleukin-6, which also activates B cells, stimulates hepatocytes to produce acute phase proteins and has the properties of b-interferon.

9. Colony-stimulating factors that promote the formation of granulocytes and monocytes in the bone marrow.

10. Tumor necrosis factor (TNF), which is not only truly capable of causing tumor necrosis, but also plays a significant role in the development of inflammation. This polypeptide, consisting of 157 amino acids, in the early phase of the inflammatory reaction promotes the adhesion of neutrophils to the endothelium and thereby facilitates their penetration into the site of inflammation. It also serves as a powerful signal for the production of toxic oxygen radicals and is a stimulator of B cells, fibroblasts and endothelium (the latter two types of cells produce colony-stimulating factors).

It is clinically important that TNF, as well as interleukin-1 and interferon, suppress the activity of lipoprotein lipase, which ensures the deposition of fat in the body. That is why, in inflammatory diseases, pronounced weight loss is often observed, which does not correspond to high-calorie nutrition and preserved appetite. Hence the second name of TNF - cachectin.

Activation of macrophages, manifested by an increase in their size, a high content of enzymes, an increase in the ability to phagocytose and destroy microbes and tumor cells, can be nonspecific: due to stimulation by other (not related to the existing pathological process) microorganisms, mineral oil, lymphokines produced by T- lymphocytes, and to a lesser extent - B-lymphocytes.

Macrophages are actively involved in the resorption of bone and cartilage. Electron microscopic examination revealed macrophages at the border of the pannus and articular cartilage, closely associated with particles of digested collagen fibers. The same phenomenon was noted when macrophages came into contact with resorbable bone.

Thus, macrophages play an important role in the development of the inflammatory process, its maintenance and chronicity and can already a priori be considered as one of the main “targets” of antirheumatic therapy.

Article for the “bio/mol/text” competition: The immune system is a powerful multi-layered defense of our body, which is amazingly effective against viruses, bacteria, fungi and other pathogens from the outside. In addition, the immune system is able to effectively recognize and destroy transformed own cells, which can degenerate into malignant tumors. However, malfunctions of the immune system (for genetic or other reasons) lead to the fact that one day malignant cells take over. An overgrown tumor becomes insensitive to attacks from the body and not only successfully avoids destruction, but also actively “reprograms” protective cells to meet its own needs. By understanding the mechanisms that tumors use to suppress the immune response, we can develop countermeasures and try to shift the balance toward activating the body's own defenses to fight the disease.

This article was submitted to the competition of popular scientific works “bio/mol/text”-2014 in the “Best Review” category.

The main sponsor of the competition is the forward-thinking company Genotech.
The competition was supported by RVC OJSC.

Tumor and immunity - a dramatic dialogue in three parts with a prologue

It has long been believed that the reason for the low effectiveness of the immune response in cancer is that tumor cells are too similar to normal, healthy ones for the immune system, tuned to search for “strangers,” to recognize them properly. This precisely explains the fact that the immune system most successfully resists tumors of a viral nature (their frequency increases sharply in people suffering from immunodeficiency). However, it later became clear that this was not the only reason.

If this article deals with the immune aspects of cancer, then the work “There are no more terrible claws in the world...” You can read about the features of cancer metabolism. - Ed.

It turned out that the interaction of cancer cells with the immune system is much more diverse. The tumor does not just “hide” from attacks, it can actively suppress the local immune response and reprogram immune cells, forcing them to serve their own malignant needs.

The “dialogue” between a degenerated cell, out of control, with its offspring (that is, a future tumor) and the body develops in several stages, and if at first the initiative is almost entirely on the side of the body’s defenses, then at the end (in the event of the development of a disease) - goes to the side of the tumor. Several years ago, cancer immunologists formulated the concept of “immunoediting” ( immunoediting), describing the main stages of this process (Fig. 1).

Figure 1. Immunoediting (immunoediting) during the development of a malignant tumor.

The first stage of immunoediting is the process of elimination ( elimination). Under the influence of external carcinogenic factors or as a result of mutations, a normal cell is “transformed” - it acquires the ability to divide indefinitely and not respond to the body’s regulatory signals. But at the same time, as a rule, it begins to synthesize special “tumor antigens” and “danger signals” on its surface. These signals attract cells of the immune system, primarily macrophages, natural killer cells, and T cells. In most cases, they successfully destroy “spoiled” cells, interrupting the development of the tumor. However, sometimes among these “precancerous” cells there are several whose immunoreactivity - the ability to cause an immune response - is weakened for some reason, they synthesize fewer tumor antigens, are less recognized by the immune system and, having survived the first wave of the immune response, continue to divide.

In this case, the interaction of the tumor with the body enters the second stage, the equilibrium stage ( equilibrium). Here the immune system can no longer completely destroy the tumor, but is still able to effectively limit its growth. In such an “equilibrium” (and undetectable by conventional diagnostic methods) state, microtumors can exist in the body for years. However, such latent tumors are not static - the properties of the cells that make them up gradually change under the influence of mutations and subsequent selection: among the dividing tumor cells, those that are better able to resist the immune system receive an advantage, and eventually cells appear in the tumor - immunosuppressants. They are able not only to passively avoid destruction, but also to actively suppress the immune response. Essentially, this is an evolutionary process in which the body unwittingly “brings out” the exact type of cancer that will kill it.

This dramatic moment marks the transition of the tumor to the third stage of development - avoidance ( escape), - in which the tumor is already insensitive to the activity of cells of the immune system, moreover, it turns their activity to its benefit. It begins to grow and metastasize. It is this kind of tumor that is usually diagnosed by doctors and studied by scientists - the two previous stages occur hidden, and our ideas about them are based mainly on the interpretation of a number of indirect data.

Dualism of the immune response and its significance in carcinogenesis

There are many scientific articles describing how the immune system fights tumor cells, but an equally large number of publications demonstrate that the presence of immune system cells in the immediate tumor environment is a negative factor that correlates with accelerated cancer growth and metastasis. Within the framework of the concept of immunoediting, which describes how the nature of the immune response changes as the tumor develops, such dual behavior of our defenders finally received an explanation.

We will look at some of the mechanisms of how this happens, using macrophages as an example. The tumor uses similar techniques to deceive other cells of the innate and acquired immunity.

Macrophages - “warrior cells” and “healing cells”

Macrophages are perhaps the most famous cells of the innate immune system - it was with the study of their abilities for phagocytosis that Metchnikoff began classical cellular immunology. In the mammalian body, macrophages are the combat vanguard: being the first to detect the enemy, they not only try to destroy it on their own, but also attract other cells of the immune system to the battlefield, activating them. And after the destruction of foreign agents, they begin to actively participate in eliminating the damage caused, developing factors that promote wound healing. Tumors use this dual nature of macrophages to their advantage.

Depending on the predominant activity, two groups of macrophages are distinguished: M1 and M2. M1 macrophages (they are also called classically activated macrophages) - “warriors” - are responsible for the destruction of foreign agents (including tumor cells), both directly and by attracting and activating other cells of the immune system (for example, T-killer cells ). M2 macrophages - “healers” - accelerate tissue regeneration and ensure wound healing.

The presence of a large number of M1 macrophages in the tumor inhibits its growth, and in some cases can even cause almost complete remission (destruction). And vice versa: M2 macrophages secrete molecules - growth factors, which additionally stimulate the division of tumor cells, that is, they favor the development of malignancy. It has been experimentally shown that M2 cells (“healers”) usually predominate in the tumor environment. Even worse: under the influence of substances secreted by tumor cells, active M1 macrophages are “reprogrammed” into the M2 type, stop synthesizing antitumor cytokines such as interleukin-12 (IL12) or tumor necrosis factor (TNF) and begin to release molecules into the environment , accelerating the growth of the tumor and the germination of blood vessels that will provide its nutrition, for example, tumor growth factor (TGFb) and vascular growth factor (VGF). They stop attracting and initiating other cells of the immune system and begin to block the local (antitumor) immune response (Fig. 2).

Figure 2. M1 and M2 macrophages: their interaction with the tumor and other cells of the immune system.

Proteins of the NF-kB family play a key role in this reprogramming. These proteins are transcription factors that control the activity of multiple genes required for M1 activation of macrophages. The most important members of this family are p65 and p50, which together form the p65/p50 heterodimer, which in macrophages activates many genes associated with the acute inflammatory response, such as TNF, many interleukins, chemokines and cytokines. The expression of these genes attracts more and more immune cells, “highlighting” the area of inflammation for them. At the same time, another homodimer of the NF-kB family - p50/p50 - has the opposite activity: by binding to the same promoters, it blocks their expression, reducing the degree of inflammation.

Both activities of NF-kB transcription factors are very important, but the balance between them is even more important. It has been shown that tumors specifically release substances that disrupt p65 protein synthesis in macrophages and stimulate the accumulation of the p50/p50 inhibitory complex. In this way (in addition to a number of others), the tumor turns aggressive M1-macrophages into unwitting accomplices of its own development: M2-type macrophages, perceiving the tumor as a damaged area of tissue, turn on the restoration program, but the growth factors they secrete only add resources for tumor growth. This completes the cycle - the growing tumor attracts new macrophages, which are reprogrammed and stimulate its growth instead of destruction.

Reactivation of the immune response is a current direction in anticancer therapy

Thus, in the immediate environment of tumors there is a complex mixture of molecules, both activating and inhibiting the immune response. The prospects for the development of a tumor (and therefore the prospects for the survival of the organism) depend on the balance of the ingredients of this “cocktail”. If immunoactivators predominate, it means that the tumor has not coped with the task and will be destroyed or its growth will be greatly inhibited. If immunosuppressive molecules predominate, this means that the tumor was able to pick up the key and will begin to progress rapidly. By understanding the mechanisms that allow tumors to suppress our immune system, we can develop countermeasures and shift the balance toward eliminating tumors.

Experiments show that the “reprogramming” of macrophages (and other cells of the immune system) is reversible. Therefore, one of the promising areas of onco-immunology today is the idea of “reactivating” the patient’s own cells of the immune system in order to enhance the effectiveness of other treatment methods. For some types of tumors (for example, melanomas) this allows achieving impressive results. Another example discovered by Medzhitov's group is the common lactate, a molecule that is produced when there is a lack of oxygen in fast-growing tumors due to the Warburg effect. This simple molecule stimulates the reprogramming of macrophages, causing them to support tumor growth. Lactate is transported into macrophages through membrane channels, and potential therapy is to block these channels.

Carry out phagocytosis.
The antigen is processed, and then its peptides are recommended (presented) to T helper cells, supporting the implementation of the immune response (Fig. 6).

Phagocytosis

see Phagocytosis

The main property of a macrophage (Fig. 4) is the ability for phagocytosis - selective endocytosis and further destruction of objects containing pathogen-associated molecular templates or attached opsonins (Fig. 5, 6).

Macrophage receptors

Macrophages on their surface express receptors that provide adhesion processes (for example, CDllc and CDllb), perception of regulatory influences and participation in intercellular interaction. Thus, there are receptors for various cytokines, hormones, and biologically active substances.

Bacteriolysis

see Bacteriolysis

Antigen presentation

see Antigen presentation

While the captured object is being destroyed, the number of pattern recognition receptors and opsonin receptors on the macrophage membrane significantly increases, which allows phagocytosis to continue, and the expression of class II major histocompatibility complex molecules involved in presentation processes also increases (recommendations) antigen to immunocompetent cells. In parallel, the macrophage synthesizes preimmune cytokines (primarily IL-1β, IL-6 and tumor necrosis factor α), which attract other phagocytes to work and activate immunocompetent cells, preparing them for the upcoming antigen recognition. The remains of the pathogen are removed from the macrophage by exocytosis, and immunogenic peptides in complex with HLA II arrive on the cell surface to activate T helper cells, i.e. maintaining the immune response.

Macrophages and inflammation

The important role of macrophages in aseptic inflammation, which develops in foci of non-infectious necrosis (in particular, ischemic), is well known. Thanks to the expression of receptors for “garbage” (scavenger receptor), these cells effectively phagocytose and neutralize elements of tissue detritus.

Also, it is macrophages that capture and process foreign particles (for example, dust, metal particles) that enter the body for various reasons. The difficulty of phagocytosis of such objects is that they are absolutely devoid of molecular templates and do not fix opsonins. To get out of this difficult situation, the macrophage begins to synthesize components of the intercellular matrix (fibronectin, proteoglycans, etc.), which envelop the particle, i.e. artificially creates such surface structures that are easily recognized. Material from the site http://wiki-med.com

It has been established that due to the activity of macrophages, a restructuring of metabolism occurs during inflammation. Thus, TNF-α activates lipoprotein lipase, which mobilizes lipids from the depot, which, with prolonged inflammation, leads to weight loss. Due to the synthesis of pre-immune cytokines, macrophages are able to inhibit the synthesis of a number of products in the liver (for example, TNF-α inhibits the synthesis of albumin by hepatocytes) and increase the formation of acute-phase proteins (primarily due to IL-6), related mainly to globulin fraction. Such repurposing of hepatocytes, along with an increase in the synthesis of antibodies (immunoglobulins), leads to a decrease in the albumin-globulin ratio, which is used as a laboratory marker of the inflammatory process.

In addition to the classically activated macrophages discussed above, there is a subpopulation of alternatively activated macrophages that provide the wound healing process and repair after an inflammatory reaction. These cells produce a large number of growth factors - platelet, insulin, growth factors, transforming growth factor β and vascular endothelial growth factor. Alternatively activated macrophages are formed under the influence of the cytokines IL-13 and IL-4, i.e. in conditions of implementation of a predominantly humoral immune response.

what are macrophages?
antibacterial immunity is
main functions of macrophages:
macrophage surface receptors
what are microphages in the lungs

Main articles: Nonspecific cellular immunity, Antibody-dependent cytotoxicity

Functions of macrophages

Macrophages perform the following functions:

Carry out phagocytosis.
They process the antigen and then recommend (present) its peptides to T helper cells, supporting the immune response (Fig.
Perform a secretory function consisting in the synthesis and release of enzymes (acid hydrolases and neutral proteinases), complement components, enzyme inhibitors, components of the intercellular matrix, biologically active lipids (prostaglandins and leukotrienes), endogenous pyrogens, cytokines (IL-1β, IL- 6, TNF-α, etc.).
They have a cytotoxic effect on target cells provided that the antithesis is fixed on them and appropriate stimulation from T-lymphocytes (the so-called antibody-dependent cell-mediated cytotoxicity reactions).
Changes metabolism during inflammation.
They take part in aseptic inflammation and destruction of foreign particles.
Provides wound healing process.

Phagocytosis

Macrophage receptors

see Innate immune receptors#Phagocyte receptors

To detect such objects, macrophages contain on their surface template recognition receptors (in particular, the mannose-binding receptor and the receptor for bacterial lipopolysaccharides), as well as receptors for opsonins (for example, for C3b and Fc fragments of antibodies).

Macrophages on their surface express receptors that provide adhesion processes (for example, CDllc and CDllb), perception of regulatory influences and participation in intercellular interaction.

Thus, there are receptors for various cytokines, hormones, and biologically active substances.

Bacteriolysis

see Bacteriolysis

Antigen presentation

see Antigen presentation

In parallel, the macrophage synthesizes preimmune cytokines (primarily IL-1β, IL-6 and tumor necrosis factor α), which attract other phagocytes to work and activate immunocompetent cells, preparing them for the upcoming antigen recognition. The remains of the pathogen are removed from the macrophage by exocytosis, and immunogenic peptides in complex with HLA II arrive on the cell surface to activate T helper cells, i.e.

maintaining the immune response.

Macrophages and inflammation

The important role of macrophages in aseptic inflammation, which develops in foci of non-infectious necrosis (in particular, ischemic), is well known.

Macrophages in the blood

Thanks to the expression of receptors for “garbage” (scavenger receptor), these cells effectively phagocytose and neutralize elements of tissue detritus.

Also, it is macrophages that capture and process foreign particles (for example, dust, metal particles) that enter the body for various reasons.

The difficulty of phagocytosis of such objects is that they are absolutely devoid of molecular templates and do not fix opsonins. To get out of this difficult situation, the macrophage begins to synthesize components of the intercellular matrix (fibronectin, proteoglycans, etc.), which envelop the particle, i.e. artificially creates such surface structures that are easily recognized. Material from the site http://wiki-med.com

It has been established that due to the activity of macrophages, a restructuring of metabolism occurs during inflammation.

Thus, TNF-α activates lipoprotein lipase, which mobilizes lipids from the depot, which, with prolonged inflammation, leads to weight loss. Due to the synthesis of pre-immune cytokines, macrophages are able to inhibit the synthesis of a number of products in the liver (for example, TNF-α inhibits the synthesis of albumin by hepatocytes) and increase the formation of acute-phase proteins (primarily due to IL-6), related mainly to globulin fraction.

Such repurposing of hepatocytes, along with an increase in the synthesis of antibodies (immunoglobulins), leads to a decrease in the albumin-globulin ratio, which is used as a laboratory marker of the inflammatory process.

These cells produce a large number of growth factors - platelet, insulin, growth factors, transforming growth factor β and vascular endothelial growth factor. Alternatively activated macrophages are formed under the influence of the cytokines IL-13 and IL-4, i.e. in conditions of implementation of a predominantly humoral immune response.

Material from the site http://Wiki-Med.com

On this page there is material on the following topics:

how can a macrophage suppress an antigen?
macrophage analysis
performs the function of a macrophage
what are microphages in the blood responsible for?
macrophages increased cause

Macrophage receptors

The surface of macrophages contains a large set of receptors that ensure the participation of cells in a wide range of physiological reactions, including the innate and adaptive immune response.

First of all, MFs are expressed on the membrane pattern recognition receptors of innate immunity, ensuring recognition of PAMS of most pathogens and OAMS - molecular structures associated with life-threatening influences and situations, primarily stress proteins.

Leading PRR MN/MF are Toll-like and NOD receptors.

The surface of these cells contains all known TLRs expressed on the plasma membranes of cells: TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10. The cytoplasm contains intracellular TLR3, TLR7, TLR8, TLR9, as well as NOD1 and NOD2 receptors.

The binding of bacterial LPS by TLR4 MF receptors is mediated by the membrane protein CD14, which is a marker of MF.

CD14 interacts with the bacterial LPS-LPS-binding protein complex, which facilitates the interaction of LPS with TLR4.

The surface of monocytes contains aminopeptidase N (CD13), which also belongs to the PRR of monocytes, but is absent in MF. The CD13 molecule has the ability to bind the envelope proteins of some viruses.

A large amount is expressed on MN/MF phagocytic receptors.

This lectin receptors (Firstly mannose receptor , Dectin-1 and DC-SIGN), as well as scavenger receptors , with the help of which it is carried out direct recognition pathogens and other objects of phagocytosis.

(See Part II, Chapter 2 “Innate immune receptors and molecular structures recognized by them”). Ligands for scavenger receptors are components of a number of bacteria, including staphylococci, neisseria, listeria, as well as modified structures of their own cells, modified low-density lipoproteins and fragments of apoptotic cells.

The mannose receptor mediates the uptake of MN/MF in many bacterial species, including Mycobacteria, Leismania, Legionella, Pseudomonas aeruginosa, and others.

The structure of this receptor determines its ability to bind peptidoglycan of the bacterial cell wall with high affinity. Interestingly, cytokines that activate MF (IFN-γ, TNF-α) cause inhibition of the synthesis of this receptor and a decrease in its expression. In contrast, anti-inflammatory corticosteroids increase the synthesis of the mannose receptor and its expression on MF.

Vitamin D stimulates the expression of this receptor.

Special receptors for binding advanced glycation end products (AGEs) are also found on the membrane of macrophages, which progressively accumulate in tissues as the body ages and accumulates rapidly in diabetes. These glycosylation products cause tissue damage by cross-linking proteins.

Macrophages, which have special receptors for AGEs, capture and degrade proteins modified by these products, thereby preventing the development of tissue destruction.

Almost all phagocytic receptors are also expressed on MN/MF, with the help of which mediated recognition of pathogens opsonized by antibodies and complement and other foreign particles and cells.

These primarily include Fc receptors And receptors for activated complement fragments (CR1, CR3 And CR4 , and receptors for the C1q fragment and anaphylatoxins C3a and C5a) .

Hc receptors provide recognition and stimulate phagocytosis of objects opsonized by antibodies.

There are three different receptors for IgG binding: FcγRI, FcγRII and FcγRIII (CD64, CD32 and CD16, respectively).

FcγRI is the only one of these receptors that has high affinity for monomeric IgG and is expressed almost exclusively on macrophages.

In contrast, the low-affinity FcγRII receptor is expressed on monocytes and macrophages. FcγRIII is also expressed on monocytes and macrophages, has low affinity for IgG and binds primarily immune complexes or aggregated IgG. All three types of receptors mediate the phagocytosis of bacteria and other cells opsonized by IgG and participate in the antibody-dependent cellular cytotoxicity of natural killer cells (ADCCT) and phagocytes towards target cells carrying antigen-antibody complexes on the membrane.

Activation of macrophages through Fc receptors leads to lysis of target cells due to the release of a number of mediators (primarily TNF-α), which cause the death of these cells. Some cytokines (IFN-γ and GM-CSF) can increase the effectiveness of ADCT with the participation of monocytes and macrophages.

An important group of receptors are receptors for chemokines and other chemoattractants.

In addition to the receptors for C3a, C5a, C5b67, which cause chemotaxis of MN/MF to the site of inflammation or infection, the surface of these cells contains receptors for inflammatory chemokines (CXCR1, CCR1, CCR2, CCR3, CCR4, CCR5, CCR8, etc.).

Inflammatory chemokines produced by epithelial cells and vascular endothelial cells, as well as resident MFs located at the site of the reaction that have been activated by contact with pathogens or tissue damage, stimulate the chemotaxis of new cells involved in the defense.

Neutrophils are the first to enter the site of inflammation; later, monocyte-macrophage infiltration begins, caused by contact of the chemokine receptors of these cells with the corresponding ligands.

A large amount is expressed on MN/MF membranes glycoprotein receptors for cytokines.

The binding of cytokines to the corresponding receptors serves as the first link in the chain of transmission of the activation signal to the cell nucleus. Most specific for MN/MF receptor for GM-CSF (CD115) . The presence of this receptor makes it possible to differentiate MNs and their precursors from granulocyte cells that lack this receptor.

Particularly important for MN/MF are receptors for IFN-γ (IFNγRI and IFNγRII) , because through them, many functions of these cells are activated .

There are also receptors for proinflammatory cytokines (IL-1, IL-6, TNF-α, IL-12, IL-18, GM-CSF), activating, including autocrine, MN/MF involved in the inflammatory response.

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Tissue macrophages

Several populations of tissue macrophages, descendants of mononuclear phagocytes, have also been characterized for surface markers and biological functions. Granulomas usually contain epithelioid cells, which appear to be formed from blood monocytes activated during an immune response to a foreign antigen, such as in a delayed-type cutaneous hypersensitivity reaction.

Epithelioid cells have many of the morphological features of macrophages and carry Fc and S3 receptors. In general, they have less phagocytic activity than macrophages. Another cell type, multinucleated giant cells, appears to be formed by macrophage fusion rather than by nuclear division in the absence of cytoplasmic division.

Two types of such cells have been identified: Langhans cells, with a relatively small number of nuclei at the periphery of the cytoplasm, and foreign body cells, in which many nuclei are distributed throughout the cytoplasm.

The fate of monocytes penetrating into areas of inflammation can be different: they can turn into sedentary macrophages, transform into epithelioid cells, or merge with other macrophages and become multinucleated giant cells.

When inflammation subsides, macrophages disappear - how is still unclear. Their number may decrease as a result of either death or their migration from the site of inflammation.

Kupffer cells are resident macrophages of the liver. They border the bloodstream, which allows them to constantly come into contact with foreign antigens and other immunostimulating agents. The anatomical location between the veins carrying blood from the gastrointestinal tract and the liver's own bloodstream means that Kupffer cells are among the first in a series of mononuclear phagocytes to interact with immunogens absorbed from the intestine.

Macrophages in the blood

Like other tissue macrophages, Kupffer cells are long-lived descendants of monocytes that take up residence in the liver and differentiate into macrophages.

They live in the liver for an average of about 21 days. The most important function of Kupffer cells is to absorb and degrade dissolved and insoluble materials in the portal blood.

Kupffer cells play a critical role in clearing the bloodstream of a variety of potentially harmful biological materials, including bacterial endotoxins, microorganisms, activated clotting factors, and soluble immune complexes. In accordance with their function, Kupffer cells contain an unusually large number of lysosomes containing acid hydrolases and capable of active intracellular digestion.

Previously, it was believed that the ability of Kupffer cells to perform any functions other than phagocytic ones is relatively low.

Therefore, it could be thought that by absorbing and digesting large, potentially immunogenic compounds, allowing only small, difficult-to-absorb fragments to remain in the bloodstream, Kupffer cells are involved in creating a state of tolerance. However, recent in vitro studies of highly purified Kupffer cells have shown that they are capable of functioning as antigen-presenting cells in many known T cell activating assays. Apparently, the anatomical and physiological features of the normal hepatic microenvironment impose restrictions on the activity of Kupffer cells, preventing them from participating in the induction of an immune response in vivo.

Alveolar macrophages line the alveoli and are the first immunologically competent cells to engulf inhaled pathogens. It was therefore important to find out whether macrophages from an organ such as the lungs, which have an extensive epithelial surface that is constantly in contact with external antigens, are capable of functioning as auxiliary cells. Macrophages located on the surface of the alveoli are ideally positioned to interact with antigen and then present it to T lymphocytes.

Guinea pig alveolar macrophages have been shown to be highly active supporting cells in both antigen- and mitogen-induced T-cell proliferation assays.

It was then shown that an antigen injected into an animal's trachea could induce a primary immune response and selectively enrich antigen-specific T cells in the lungs.