Macrophage-monocyte system Main stages of development, phenotypic characteristics, properties of apk. Modern detection methods

am, supporting the implementation of the immune response (Fig. 6).

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

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

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 produces the synthesis of pre-immune cytokines (primarily IL-1β, IL-6 and tumor necrosis factor α), which attract other phagocytes to work and activate immunocompetent cells, preparing them for 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.

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

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 synthesis

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 that can degenerate into malignant tumors. However, malfunctions 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 in this article we're talking about about the immune aspects of cancer, then in 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 cancer cells with the immune system is much more versatile. 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 just as many publications demonstrate that the presence of immune system cells in the immediate tumor environment is negative factor, which 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 secrete environment molecules that accelerate tumor growth and germination blood vessels, which 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.

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 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 activity of the immune system, malignant tumors develop uncontrollably and the level of viral infections. 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.

Macrophages(from ancient Greek μακρός - large, and φάγος - eater (synonyms: histiocyte-macrophage, histophagocyte, macrophagocyte, megalophage-eater)), polyblasts, cells of mesenchymal nature in the animal body, capable of actively capturing and digesting bacteria, residues dead cells and other particles foreign or toxic to the body. The term “macrophages” was introduced by Mechnikov.

Macrophages include blood monocytes, histiocytes connective tissue, endothelial cells of the capillaries of the hematopoietic organs, Kupffer cells of the liver, cells of the wall of the alveoli of the lung (pulmonary macrophages) and the wall of the peritoneum (peritoneal macrophages).

It has been established that in mammals, macrophage precursors are formed in the bone marrow. The cells of the reticular tissue of the hematopoietic organs, which are combined with macrophages into the reticuloendothelial (macrophagic) system, which performs a protective function in the body, also have active phagocytic properties.

Morphology

The main cell type of the mononuclear phagocyte system. These are large (10 - 24 microns) long-lived cells with a well-developed lysosomal and membrane apparatus. On their surface there are receptors for the Fc fragment of IgGl and IgG3, C3b fragment C, receptors of B and T lymphocytes, complement, other interleukins and histamine.

Tissue macrophages

In fact, a monocyte becomes a macrophage when it leaves the vascular bed and penetrates the tissue.

Depending on the type of tissue, the following types of macrophages are distinguished.

· Histiocytes - macrophages of connective tissue; component of the reticuloendothelial system.

· Kupffer cells - otherwise endothelial stellate cells of the liver.

· Alveolar macrophages - otherwise, dust cells; located in the alveoli.

· Epithelioid cells - components of granulomas.

· Osteoclasts are multinucleated cells involved in bone resorption.

· Microglia are cells of the central nervous system that destroy neurons and absorb infectious agents.

Macrophages of the spleen

Identification of macrophages

macrophages contain numerous cytoplasmic enzymes and can be identified in tissues by histochemical methods that detect these enzymes. Some enzymes, such as muramidase (lysozyme) and chymotrypsin, can be detected by a labeled antibody test (immunohistochemistry), which uses antibodies against the enzyme proteins. Such monoclonal antibodies against various CD antigens are widely used to identify macrophages.

Functions of macrophages

Macrophage functions include phagocytosis, antigen processing, and interaction with cytokines.

Phagocytosis

· Non-immune phagocytosis: macrophages are able to phagocytose foreign particles, microorganisms and the remains of damaged cells directly, without inducing an immune response. However, phagocytosis of microorganisms and their destruction are greatly facilitated by the presence of specific immunoglobulins, complement and lymphokines, which are produced by immunologically activated T lymphocytes.

· Immune phagocytosis: macrophages have surface receptors for the C3b and Fc fragment of immunoglobulins. Any particles that are coated with immunoglobulin or complement (opsonized) are phagocytosed much more easily than “naked” particles.

· “Processing” of antigens: macrophages “process” antigens and present them to B- and T-lymphocytes in the required form; This cellular interaction involves the simultaneous recognition by lymphocytes of MHC molecules and “processed antigens” found on the surface of macrophages.

· Interaction with cytokines: Macrophages interact with cytokines produced by T lymphocytes to protect the body against certain damaging agents. A typical result of such interaction is the formation of granulomas. Macrophages also produce cytokines, including interleukin-1, interferon-β, and T- and B-cell growth factors. Various interactions of lymphocytes and macrophages in tissues manifest themselves morphologically during chronic inflammation.

The role of macrophages is not limited to the secretion of IL-1. In these cells a number of biologically synthesized active substances, each of which contributes to inflammation. These include: esterases, proteases and antiproteases; lysosomal hydrolases - collagenase, alastase, lysozyme, α-macroglobulin; monokines - IL-1, colony-stimulating factor, fibroblast growth-stimulating factor; anti-infective agents - interferon, transferrin, transcobalamin; complement components: C1, C2, C3, C4, C5, C6; Arachidonic acid derivatives: prostaglandin E2, thromboxane A2, leukotrienes.

Macrophages are members of the immune system that are vital for the development of nonspecific defense mechanisms that provide the first line of defense against. These large immune cells are present in almost all tissues and actively remove dead and damaged cells, bacteria, and cellular debris from the body. The process by which macrophages engulf and digest cells and pathogens is called.

Macrophages also assist in cellular or adaptive immunity by capturing and presenting information about foreign antigens to immune cells called lymphocytes. This allows the immune system to better defend against future attacks by the same invaders. In addition, macrophages are involved in other important functions in the body, including hormone production, immune regulation, and wound healing.

Macrophage phagocytosis

Phagocytosis allows macrophages to get rid of harmful or unwanted substances in the body. Phagocytosis is a form in which a substance is taken up and destroyed by a cell. This process is initiated when a macrophage targets a foreign substance with the help of antibodies. Antibodies are proteins produced by lymphocytes that bind to a foreign substance (antigen), bringing it into the cell for destruction. Once the antigen is detected, the macrophage sends projections that surround and engulf the antigen (dead cells, etc.), surrounding it in a vesicle.

The internalized vesicle containing the antigen is called a phagosome. in the macrophage they merge with the phagosome, forming the phagolysosome. Lysosomes are membrane sacs of hydrolytic enzymes formed that are capable of digesting organic material. The enzyme contents in the lysosomes are released into the phagolysosome, and the foreign substance is quickly degraded. The degraded material is then expelled from the macrophage.

Macrophage development

Macrophages develop from white blood cells called monocytes. Monocytes are the largest type of white blood cell. They have a large solitary, which is often kidney-shaped. Monocytes are produced in the bone marrow and circulate in one to three days. These cells exit the blood vessels, passing through the endothelium of the blood vessels to enter the tissues. Once they reach their destination, monocytes turn into macrophages or other immune cells called dendritic cells. Dendritic cells help in the development of antigenic immunity.

Macrophages, which differ from monocytes, are specific to the tissue or organ in which they are localized. When there is a need for more macrophages in a particular tissue, living macrophages produce proteins called cytokines, causing monocytes to respond to develop into the required type of macrophage. For example, macrophages that fight infection produce cytokines that promote the development of macrophages that specialize in fighting pathogens. Macrophages, which specialize in wound healing and tissue repair, develop from cytokines produced in response to tissue damage.

Function and location of macrophages

Macrophages are found in almost all tissues of the body and perform a number of functions outside of the immune system. Macrophages help in the production of sex hormones in the male and female reproductive organs. They promote the development of networks of blood vessels in the ovary, which is vital for the production of the hormone progesterone. Progesterone plays an important role in the implantation of the embryo into the uterus. Additionally, macrophages present in the eye help develop the networks of blood vessels necessary for proper vision. Examples of macrophages that are found elsewhere in the body include:

• Central nervous system: microglia are glial cells found in nerve tissue. These extremely small cells patrol the brain and spinal cord, removing cellular waste and protecting against microorganisms.
• Adipose tissue: Macrophages in fat tissue protect against microbes and also help fat cells maintain the body's sensitivity to insulin.
• Integumentary system: Langerhans cells are macrophages in the skin that serve immune function and help in the development of skin cells.
• Kidneys: macrophages in the kidneys help filter microbes from the blood and promote the formation of ducts.
• Spleen: Macrophages in the red pulp of the spleen help filter damaged red blood cells and microbes from the blood.
• Lymphatic system: macrophages stored in the central region lymph nodes, filter lymph with microbes.
• Reproductive system: macrophages help in the development of germ cells, the embryo and the production of steroid hormones.
• Digestive system: Macrophages in the intestine control the environment that protects against microbes.
• Lungs: alveolar macrophages, remove germs, dust and other particles from respiratory surfaces.
• Bone: macrophages in bone can develop into bone cells called osteoclasts. Osteoclasts help reabsorb and assimilate bone components. Immature cells from which macrophages are formed are found in the non-vascular parts of the bone marrow.

Macrophages and diseases

Although the primary function of macrophages is defense against, sometimes these pathogens can evade the immune system and infect immune cells. Adenoviruses, HIV, and the bacteria that cause tuberculosis are examples of pathogens that cause disease by infecting macrophages.

In addition to these types of diseases, macrophages are associated with the development of diseases such as cardiovascular disease, diabetes, and cancer. Macrophages in the heart contribute cardiovascular diseases, helping in the development of atherosclerosis. In atherosclerosis, artery walls become thick due to chronic inflammation caused by white blood cells.

Macrophages in adipose tissue can cause inflammation, which induces insulin resistance in fat cells. This can lead to the development of diabetes. Chronic inflammation caused by macrophages can also contribute to the development and growth of cancer cells.