Written by: immune meow with picky eaters
Source: gossip Immunology
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Macrophages (English name: Macrophages, abbreviated M) are immune cells widely distributed in blood and tissues of the whole body.Macrophages can devour and kill intracellular parasites, bacteria, tumor cells, as well as self-aging and abnormal cells, and play an important role in immune defense, immune homeostasis and immune monitoring.Macrophages are a kind of phagocytes and belong to monocyte system.
Macrophages have been a hot research object for a long time because of their diversity and heterogeneity in tissue distribution.
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The origin of macrophages
The evolution of species diversity and struggle for existence have produced a complex host defense system, which relies on natural immunity, first single-celled eukaryotes, and then adaptive immunity in tissues and developing eukaryotes. Natural immunity was first expounded at the end of 19th century, and Elie Metchnikoff introduced the word "macrophage", which means "macro = big and phage = eater”。 Monocytes/macrophages are a small group of white blood cells determined by their location, phenotype, morphology and gene expression profile.
Monocytes account for 4-10% of nucleated cells in normal peripheral blood. In blood, the half-life of monocytes is less than 20 hours. For many years, it has been assumed that macrophages are completely differentiated from circulating monocytes, but the recent morphological and functional differences between these cells refute this hypothesis.
Recent research evidence shows that macrophages in most adult tissues are sown before birth, and during embryonic development, they are transferred from.yolk sacIt has the ability of self-renewal and is maintained independently of monocytes. In addition,Each organ has its own unique combination of embryos and adult macrophages..
Embryonic macrophages participate in tissue reconstruction, while adult macrophages mainly assist host defense. In addition to these differences, we also observed that embryonic macrophages and adult macrophages coexist in many different organs.
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Tissue distribution of different macrophages
According to their anatomical location and functional phenotype, macrophages can be divided intoMicroglial cell、osteoclast、pm, spleen tissue cells and interstitial connective tissue, liver interstitial connective tissue and kupffer cells.
There are also different types of macrophages in the intestine, which have different phenotypes and functions, but work together to maintain tolerance to normal intestinal flora and oral antigens.
There are also different numbers of macrophages in the secondary lymphoid organs, including macrophages in the marginal area of spleen, which inhibit the natural immunity and adaptive immunity to apoptotic cells, and sinus macrophages under the capsule of lymph nodes, which remove the virus in lymph and start the antiviral immune response.
differentMacrophages exist in immune immune immune sites., such as the brain, eyes and testicles, these parts are inTissue remodelinganddynamic balancePlay a central role. These tissue-specific macrophages devour dead cells, debris, foreign antigens and materials, organize the inflammatory process, and recruit more macrophages as needed.
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Plasticity and polarization
Macrophages are remarkable plastic cells, which can be obtained fromConversion from one phenotype to another.. Macrophage polarization is a process. Macrophages show specific phenotypes and make functional responses to microenvironment stimuli and signals encountered in each specific tissue.
Local cytokine environment can localize macrophage polarization. The two subsets of macrophages with different functions include classic activated or inflammatory (M1) and alternately activated or anti-inflammatory (M2) macrophages. This phenomenon of these two different M1/M2 phenotypes is called.Macrophage polarization.
M1 macrophageIt is usually induced by the recognition of Th1 cytokines (such as IFN-γ and T NF-α) or bacterial lipopolysaccharide (LPS). These macrophages produce and secrete high levels of proinflammatory cytokines TNF-α, IL-1α, IL-1β, IL-6, IL-12, IL-23 and COX-2, while the level of IL-10 is low.
Functionally, M1 macrophages participate in the elimination of pathogens during infection by activating nicotinamide adenine phosphodinucleotide (NADPH) oxidase system and then producing reactive oxygen species (ROS). Therefore, M1 macrophages have strong anti-microbial and anti-tumor activities, mediating tissue damage caused by reactive oxygen species, damaging tissue regeneration and wound healing. In order to prevent this kind of tissue damage, the anti-inflammatory effect of M2 macrophages inhibits the chronic inflammatory reaction by regulating the mechanism.
M2 macrophageSTAT6 is activated by IL-4 receptor α(IL-4Rα) and polarized by Th2 cytokines IL-4 and IL-13, which has anti-inflammatory effect. Besides IL-4 and IL-13, cytokines such as IL-10 can also regulate M2 polarization by activating STAT 3 through IL-10 receptor (IL-10 R).
IL-33It is a cytokine related to Th2 in IL-1 family and can induce M2 polarization. It is characterized by up-regulating arginase-1(arg-1), CCL 17 and CCL 24, thus mediating pulmonary eosinophilia and airway inflammation.
IL-21It is another Th2-related cytokine that drives M2 polarization. M2 macrophages have the characteristics of anti-inflammatory cytokines, which are characterized by low production of IL-12 and high production of IL-10 and TGF-β.
Functionally, M2 macrophages have strong phagocytosis, which can remove debris and apoptotic cells, promote tissue repair and wound healing, and promote angiogenesis and fibrosis. Therefore, generally speaking, M2 cells participate in Th2 response and parasite clearance, inhibit inflammation, promote tissue remodeling, angiogenesis, immune regulation, tumor formation and progress.
However, the M1/M2 phenotype does not reflect different phenotypic subsets of macrophages. According to the activation stimulus received, M2 macrophages can be further divided into four types.M2A, M2B, M2C and M2DDifferent subgroups of the composition.
M2aMacrophage subsets can be induced by IL-4 and IL-13, producing high levels of CD206, bait receptor IL-1 receptor II(IL-RII) and IL-1 receptor antagonist (IL-1RA).
Immune complex (ICs) and Toll-like receptor (TLR) agonists or IL-1 receptor ligands can induce M2b subgroup.M2bMacrophages simultaneously produce anti-inflammatory and pro-inflammatory cytokines IL-10, IL-1β, IL-6 and α-α.
M2cCells were induced by glucocorticoid and IL-10, and showed strong anti-inflammatory effect on apoptotic cells by releasing a large amount of IL-10 and transforming growth factor-β.
Finally, TLR agonist induced the fourth M2 macrophage through adenosine receptor agonist.M2d.
The activated receptor of adenosine then inhibits the production of pro-inflammatory cytokines, induces anti-inflammatory secretion of cytokines (high IL-10, low IL-12) and vascular endothelial growth factor (VEG F), thus providing a drug withTumor associated macrophages (TAMS)The angiogenic characteristics of the characteristic. M2 macrophages exposed to M1 signal, or conversely, induced differentiated macrophages to "repolarize" or "reprogram" is another evidence that they have high functional plasticity and can potentially pursue therapeutic goals.
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hugeMigration of phagocytes
Monocytes and macrophages migrate to the site of inflammation or injury to eliminate the initial inflammatory signal and ultimately promote wound healing and tissue repair.
This process is mainly initiated by pathogen-related molecular patterns (PAMPs) (released from invasive pathogens) and damage-related molecular patterns (DAMPs) (released from damaged or dead cells to cope with infection and injury).
In addition, antigen can activate memory T cells in tissues through secretion.manyInflammatory cytokines and chemokines are used to trigger the recruitment of macrophages. Chemokines directly participate in the migration and activation of monocytes through endothelium, and monocyte chemoattractant protein -1 (MCP-1) is a monocyte chemotactic factor, which participates in the occurrence of inflammation and induces monocyte chemotaxis and migration by interacting with CC chemotactic factor 2(CCR2) on monocytes. MCP-1 is mainly secreted by activated fibroblasts, endothelial cells, vascular smooth muscle cells (VSMC), monocytes and T cells. MCP-1, together with IL-8 or CXC ligand -8(CXCL-8), can trigger the firm adhesion of monocytes to vascular endothelial cells under blood flow conditions. Monocyte adhesion and migration across endothelium through activated venule wall is a basic immune response, which depends on the expression of adhesion molecules of chemical mediators on the surface of vein endothelium.
These adhesion molecules belong to four families:Selectin、Integrin、Immunoglobulin superfamilyandMucin-like glycoprotein.
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Antigen presentation
Antigen presenting cells, mainly macrophages, are the outposts of the immune system that starts and regulates immune response. An important feature of macrophage biology is the capture, endocytosis and expression of self or foreign antigens, which providesThe connection between innate immunity and adaptive immunity.
Macrophages reside in surrounding organs, where they monitor surrounding tissues for invading pathogens. They alert the immune system to the presence of pathogens by engulfing them, processing their antigens and presenting peptide fragments that bind to human leukocyte antigen (HLA) molecules. After antigen treatment, macrophages migrate to T cells and stimulate them. Activated macrophages express high levels of costimulatory molecules and antigen presenting molecules on their surfaces, such as CD 80, CD 86 and MHCⅠ ⅰ and ⅱ molecules. Mixed Leukocyte/Lymphocyte Reaction (MLR) is used as a basic test for determining the function of macrophages, because it measures the proliferation ability of macrophages to allogeneic T cell populations.
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Production of cytokine and chemokines
Interleukin is a kind of cytokine, which is involved in inducing adhesion molecules, matrix metalloproteinases (MMP), angiogenic factors and signal pathways, such as nuclear factor kappa B(NF-kB) and signal transduction and transcription activator (STAS) involved in tumor invasion and angiogenesis.
Activation of M1 macrophages can induce proinflammatory cytokines., including TNF-α, IL-1α, IL-1β, IL-6, IL-12, IL-18 and IL-23; Produce nitric oxide (NO), reactive oxygen species (ROS) and RNS；; Antigen presentation; Expression of CC chemokine receptors CCR1 and CCR5; Promoting T-helper type 1 (Th1) and Th17 responses provides an effective mechanism for killing.
Obviously, M1 and M2 macrophages have different chemokine profiles, while M1 macrophages expressing Th1 cell chemokines, such as CXCL9 and CXCL10.
M2 macrophages express chemokines.CCL17, CCL18, CCL22 and CCL 24. M1 macrophages express inflammatory cytokines TNF-α, IL-1β and IL-6, and together with costimulatory molecules CD 40, CD 80 and CD 86, they up-regulate MHCⅡ class II molecules to promote cytotoxic adaptive immunity.
M1 macrophages express Th1- and Th17- polarized cytokines IL-12, IL-23, IL-27 and Th1- aggregation chemokines CXCL 9, CXCL 10 and CXCL 11. On the contrary, M2 macrophages support the resolution of inflammation by transferring gene expression to anti-inflammatory molecules such as IL-10, TGF-β, IL-1R1Ⅱ and IL-1Ra. M2 macrophages also express a large number of endogenous receptors, including scavenger receptor CD 163, stabilizer -1 and type C lectin receptor CD 206, CD 301, Dectin-1 and CD 209. In addition, M2 macrophages recruit Th2, regulatory T cells (Tregs), eosinophils and basophils by secreting chemokines such as CCL 17, CCL 18, CCL 22 and CCL 24..
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Macrophage apoptosis
Apoptosis is a normal, physiological and necessary process of cell selection and survival, eliminating and removing unnecessary cells, such as aging, damaged, genetic mutation and virus-infected cells; In fact, anti-apoptosis can promote malignant transformation of normal cells.
At present, it is known that macrophage apoptosis is related to various stages of the disease related to the decline of pathogen activity, which can be regarded as a natural immune defense mechanism and strategy for the host to limit infection against intracellular pathogens.
On the contrary, many cellsPathogens have the ability to kill infected cells., destroy the host pathway, inhibit cell apoptosis, leading to necrosis. This strategy can makePathogens escape the host’s immunity and infect other nearby or distant cells.. These apoptotic infected cells also provide a link between innate immunity and acquired immunity. When professional APCs absorb apoptotic vesicles, this connection begins when bacterial products and pathogenic antigens enhance T cell activation. Similarly,Pathogens inhibit apoptosis and promote necrosis.It also impairs the presentation of bacterial antigens, which may be the mechanism of immune escape.
In atherosclerosis, macrophages die by reducing the number of cells in the lesion, which is beneficial to reduce the lesion area. In the progress of atherosclerosis and other diseases, the phagocytosis of M2 macrophages solves the problem of apoptosis and its adverse effects. This unique functional feature of M2 macrophage is caused byHigh level of scavenger receptorExpress support.
Macrophages phagocytize debris, injured cells, dead cells and apoptotic cells, and inhibit macrophages from producing pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin -1β, interleukin -6 and interleukin -8. The mechanism involves autocrine or paracrine of transforming growth factor -β(TGF-β), thus inhibiting further recruitment of monocytes and macrophages.
In addition, the phagocytosis of apoptotic cells inhibits the production of pro-inflammatory IL-12, IL-23 and IL-27 and stimulates the production of anti-inflammatory IL-10.
By limiting the phagocytosis of local inflammation, it can also protect tissues from harmful pro-inflammatory reactions, death, injury and the immunogenic content of dead cells, and throughNecrosis after apoptosis to protect the growth of lesions.
In the late stage of atherosclerosis, the phagocytic function of apoptotic cells is seriously damaged, which leads to the aggregation of macrophages and vascular smooth muscle cells, which eventually blocks the decomposition of inflammation and promotes local necrosis, inflammatory state and plaque instability.
Understanding the exact mechanism of pathogen inhibiting apoptosis can avoid natural immunity and adaptive immunity, which provides a new strategy for optimizing treatment. The idea of manipulating the host or bacterial pathway to induce more cell apoptosis, "apoptosis-promoting therapy", may help to produce a more effective immune response.
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Macrophage metabolism
Recent evidence shows that metabolism plays an important role in the formation of macrophages and the obvious polarization phenotype. Under normal, physiological and pathological conditions, macrophages face an oxygen gradient.Macrophages adapt to hypoxia by shifting their metabolic pathways to glycolysis.. In addition, the activation of hypoxia-inducible factors (HIF)-1 and -2 caused profound functional changes, including the expression of chemokines and chemokine receptors, such as CXC chemokine 4(CXCR 4), CXCL 12, angiogenesis factor and vascular endothelial growth factor (VEGF)(Biswas and Mantovani, 2012; Orihuela et al., 2016). Therefore, macrophages help to coordinate the response of tissues to oxygen gradient and hypoxia conditions.
Macrophages M1 and M2 can obviously regulate the metabolism of glucose, amino acids, iron and folic acid.After macrophage activation, its metabolic pathway changes from oxidation to glycolysis.solve. Under the action of M1 stimuli (such as LPS, Th1 cytokines and IL-12), they showed a metabolic transformation to anaerobic glycolytic pathway, while M2 stimuli (such as IL-4 and IL-13) had little effect. Macrophages activated by IFN-γ and L-PS are often associated with acute infection, so it is necessary to trigger strong antimicrobial activity quickly in hypoxic microenvironment. In this case, the anaerobic process such as glycolysis is the best way when energy is needed. Interferon-γ and lipopolysaccharide strongly induce glucose uptake and inhibit fatty acid uptake and oxidation. Therefore, glycolysis metabolism is enhanced and mitochondrial activity is decreased.
On the contrary,M2 macrophage functions, such as wound healing and tissue repair, need continuous energy supply.. This requirement is made byGlucose oxidative metabolism and fatty acid oxidationProvided, andFatty acid oxidation is the most important metabolic pathway of M2 macrophages.. M2 macrophage has the characteristics of high mitochondrial activity and oxidative phosphorylation. They show enhanced respiratory activity based on fatty acid β oxidation. Both metabolic pathways are up-regulated in the process of macrophage activation, but glycolysis is the main metabolic pathway, which can produce DNA and cell membrane synthesis substrates and promote the growth and differentiation of monocytes. It is another possibility of glycolytic metastasis of M1 macrophages to produce rapid and optimal response at the infected site.
In addition, the accumulation of citric acid in M1 macrophages is essential for the production of pro-inflammatory mediators NO, ROS, RNS and prostaglandin. Another important aspect is the metabolism of amino acids closely related to the functional phenotype of macrophages. M1 macrophages are characterized by the expression of inducible nitric oxide synthase (iNOS).The production of NO is an important anti-microbial effect. M1 macrophages are active, while M2 macrophages do not produce NO.. On the contrary, they express high levels of Arg-1 and play a role in catalyzing the production of polyamines, which are necessary for collagen synthesis, cell proliferation, fibrosis and other tissue remodeling functions. Interestingly, the production of polyamines is reported to be the driving factor of M2 polarization.
In addition, there are significant differences in iron metabolism between M1 and M2 macrophages. Although M1 macrophages express a large number of iron storage proteins, such as ferritin, the content of iron porphyrin they express is low, and ferritin is the export of iron. Compared with M1 type macrophages, M2 type macrophages have lower ferritin content, but higher ferritin content. This different iron metabolism may be related to its function. Because iron is necessary to support the growth of bacteria, the retention of iron in M1 macrophages is a kind of bacteriostasis and supports the host’s protection against infection. On the contrary, the iron released by M2 macrophages is beneficial to tissue repair, but it can cause tumor growth and metastasis.
Metabolic adaptation is an important aspect of macrophage polarization and its functional activities.
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MicroRNA involved in macrophage polarization
MicroRNA plays an important role in many aspects of macrophage biology, thus affecting many biological and pathological conditions, such as monocyte differentiation and development, macrophage polarization, infection, atherosclerosis, tumor growth, inflammatory activation, cholesterol homeostasis, cell survival and proliferation, and phagocytosis.
MiRNA-24, miRNA-30b, miRNA-142-3p and miRNA-199a-5p can inhibit the differentiation of monocytes into macrophages.
M1 macrophage polarizationMiRNA-125, miRNA-146, miRNA-155, miRNA-7a/f and miRNA-378 are needed, andM2 polarizationThen miRNA-let-7c/e, miRNA-9, miRNA-21, miRNA-146, miRNA-147, miRNA-187 and miRNA-223 are needed.
In addition, miRNA-342-5p promotes NO synthesis, and IL-6 provides pro-inflammatory signals for macrophages. Although miR-21 has been proved to have both pro-inflammatory and anti-inflammatory effects, its anti-inflammatory effect is more prominent. MiR-155 and miR-142-3p inhibited the proliferation of macrophages compared with let-7a. MiR-155 can promote and prevent apoptosis at the same time, while miR-21 and let-7e negatively regulate the apoptosis of macrophages.
Main references
Abbas Shapouri Moghaddam，doi:10.1002/jcp.26429，2018
Thomas A. Wynn，Nature，doi:10.1038/nature12034，2013
Nicole J. Horwood，Clinic Rev Allerg Immunol，doi:10.1007/s12016-015-8519-2
