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Macrophage, M1 & M2, Polarization and Function

What is a Macrophage?

Macrophages are a type of white blood cell of the immune system that engulfs and digests cellular debris, foreign substances, pathogens and cancer cells in a process known as phagocytosis (Wikipedia Contributors, 2020). The action of phagocytosis involves the engulfment of an organism or foreign molecule into the cell.

These cells also produce inflammatory molecules and mediators known as cytokines, which are involved in the signalling of other immune cells to the site of infection. Examples of these cytokines include TNF (tumour necrosis factor), IL-1, IL-6, IL-8 and IL-12 (Arango Duque & Descoteaux, 2014).

They also produce antimicrobial mediators such as complement proteins and reactive oxygen species which can kill the phagocytosed pathogen (Flannagan et al., 2015).Macrophages are derived from blood monocytes, a non-specialized cell of the innate immune system in the bone marrow and differentiate into macrophages based on the stimuli at the site of infection (Hirayama et al., 2017).

What is a Macrophage?

Macrophage and monocytes are both types of white blood cells. macrophages are a type of phagocyte, which means they engulf and destroy foreign particles, while monocytes are a type of lymphocyte, which means they help to fight infection.

Macrophages are larger than monocytes and have more cytoplasm. Macrophages are found in all tissues of the body, while monocytes are found in the bloodstream. macrophages help to protect the body from infection by destroying bacteria and viruses, while monocytes help to fight infection by producing antibodies. macrophages can also kill cancer cells, while monocytes cannot.

What do marcophages secrete?

Macrophages are a type of white blood cell that play a key role in the immune response. Part of their job is to eat and kill bacteria or viruses. When macrophages kill bacteria or viruses, they secrete cytokines and chemokines. Cytokines are proteins that help to regulate the immune response, while chemokines are proteins that help to attract other immune cells to the site of infection.

Macrophages secrete a variety of different cytokines and chemokines, all of which play an important role in the immune response. macrophage-derived cytokines and chemokines can be divided into three main categories: pro-inflammatory, anti-inflammatory, and regulatory. Pro-inflammatory cytokines and chemokines help to initiate the inflammatory response, while anti-inflammatory cytokines and chemokines help to resolve it.

Regulatory cytokines and chemokines help to modulate the immune response. macrophage-derived cytokines and chemokines play an important role in both the initiation and resolution of the immune response. macrophage-derived cytokines and chemokines are important mediators of the immune response, and they play a key role in protecting the body from infection. macrophage-derived cytokines and chemokines can be divided into three main categories: pro-inflammatory, anti-inflammatory, and regulatory.

Morphology of macrophages

One way to study macrophage morphology is through staining. This involves using dyes to color the cells so that they can be more easily seen under a microscope. There are many different types of staining techniques, each of which can reveal different aspects of macrophage morphology.

One common staining technique is called Wright-Giemsa staining. This method stains the cells with a mixture of dyes, which makes the macrophages appear purple or blue. This staining technique is often used to study the structure of macrophage cell membranes.

Another staining method is called May-Grunwald Giemsa staining. This method uses a different mixture of dyes, which makes the macrophages appear pink or red. This staining technique is often used to study the internal structure of macrophages, such as the location of their nucleus and other organelles.

No matter which staining technique is used, studying macrophage morphology can give important insights into how these cells work to protect the body from disease.

M1 & M2 macrophages

Macrophages can be differentiated into three types, M1 and M2

M1 macrophages

M1 macrophages are pro-inflammatory and have a role in degradation of pathogens and damaged cells. They secrete pro-inflammatory cytokines and aid in the pro-inflammatory immune response (Wikipedia Contributors, 2020b).

M2 macrophages

On the other hand, M2 macrophages are anti-inflammatory and are involved in tissue-repair and halting the immune response. M2 macrophages are associated with tissue repair and the production of anti-inflammatory molecules to turn the pro-inflammatory microenvironment into a more anti-inflammatory one.

The types of molecules that they produce are IL-2, IL-4, TGF-beta and IL-10. In most cases the M2 macrophages aid in dampening down the immune response and prevent an excessive immune response, however, in some cases, these macrophages can lead to the formation of tumours as they stimulate the over-production of cell division (Ley, 2017).

Regulatory macrophages (Mregs)

M2b, sometimes known as regulatory macrophages (Mregs), produce significant amounts of IL-10 and little amounts of IL-12. Deactivated macrophages, M2c, release substantial quantities of IL-10 and TGF-β.

M2c are induced by glucocorticoids and TGF-β. M2d are pro-angiogenic cells that secrete IL-10, TGF-β, and vascular endothelial growth factor and are activated by the A2 adenosine receptor agonist IL-6 (A2R).

Macrophage markers

M1 Macrophage Markers M2 Macrophage Markers

CD80

CD206

CD86

CD163

CD64

CD68

CD32

Macrophage function

Macrophages recognise pathogens with the use of pattern recognition receptors which recognise specific molecules on the surface of pathogens. The type of PRR on the surface of macrophages is called a toll-like receptor (TLR).

Once the macrophage has recognised a specific molecule on the surface of the pathogen such as LPS, peptidoglycan, flagellin, they phagocytose these pathogens and release several different types of pro-inflammatory molecules that are involved in recruiting different immune cells to the site of infection to aid in removing the pathogen or foreign cell (Hirayama et al., 2017)..

Macrophages migrate to and circulate almost every tissue and are constantly patrolling for pathogens or eliminating dead cells. Macrophages differentiate based on the tissue that they reside in. The table below conveys the various types of differentiated macrophages in tissues.

Alveolar macrophages

Alveolar macrophages are lung macrophages that dwell in the alveoli. These macrophages are essential for removing disease, toxic, and allergic particles that have evaded the respiratory tract's mechanical barriers. Furthermore, alveolar macrophages assist maintain the lungs clean and clear by removing dead and dying cells, as well as other trash.

Tumour associated macrophages (TAMs)

Tumor-associated macrophages (TAMs) play a key role in tumor metastasis by creating an immunosuppressive tumor microenvironment (TME). TAMs produce cytokines, chemokines, growth factors, and trigger the release of inhibitory immune checkpoint proteins in T cells. This results in the suppression of T cell function and the promotion of tumor growth and metastasis. TAMs are macrophages that have been recruited by tumors to the TME to create an immunosuppressive environment.

Macrophages in the Neuroblastoma Tumour Microenvironment

Aggressive NB often displays a highly vascular and immunosuppressive TME predominantly occupied by macrophages (Apps, et al, 2013). This environment promotes their polarisation into “tumour-associated macrophages” (TAMs) which display a phenotypic and functional M2 profile.

M2 macrophages orchestrate many important anti-inflammatory functions such as tissue-repair, angiogenesis and fibrosis in times of injury, however they can have a pathogenic role in tumour formation and progression (Belgiovine, et al, 2016). They often aid in negative processes such as tumour invasion, matrix degradation and suppression of the adaptive immune system (Shapouri‐Moghaddam, et al, 2018).

CD86 macrophage

One of the molecules involved in costimulating T cells is called CD86, also known as B7-2. CD86 is a type I membrane protein that is a member of the immunoglobulin superfamily. It is expressed on antigen-presenting cells (including macrophages, B cells, and DCs) to provide the costimulatory signals necessary for T cell activation.

When a macrophage encounters a pathogen, it will phagocytose the pathogen and then present pieces of it (antigens) on its surface. CD86 is expressed on the surface of macrophages and helps to deliver the costimulatory signals that activate T cells. T cells then help to coordinate the immune response and eliminate the pathogen.

Without CD86, macrophages would be unable to properly costimulate T cells and the immune response would be compromised. Therefore, CD86 is an essential molecule for macrophage function and overall immune system.

Macrophages in atherosclerosis

Macrophages play an important role in atherosclerotic lesions. They actively participate in lipoprotein ingestion and accumulation, giving rise to foam cells filled with lipid droplets. The accumulation of foam cells contributes to lipid storage and atherosclerotic plaque growth. macrophages are important in the development and progression of atherosclerosis and can be a target for therapeutic interventions.

Macrophage polarization

There are two main types of macrophage: M1 and M2. M1 macrophages are pro-inflammatory and help to fight infection, while M2 macrophages are anti-inflammatory and help to promote healing.

Macrophages can become polarized into either an M1 or M2 state in response to different stimuli. For example, exposure to bacterial products or cytokines (signaling molecules produced by immune cells) will trigger the M1 polarization, while exposure to viruses or glucocorticoids (steroid hormones that are released in response to stress) will trigger the M2 polarization.

Once a macrophage has been polarized into an M1 or M2 state, it will remain in that state for the rest of its life. This is because the M1 and M2 states are characterized by different gene expression patterns. M1 macrophages, for example, express high levels of pro-inflammatory cytokines such as IL-6 and TNF-alpha, while M2 macrophages express high levels of anti-inflammatory cytokines such as IL-10 and IL-1RA.

The M1 and M2 states are not mutually exclusive. Macrophages can exist in a mixed state, where they express both M1 and M2 genes. However, they will usually be skewed towards one state or the other depending on the stimuli they are exposed to.

Haemosiderin-laden macrophages

Macrophages with haemosiderin in their cytosol are a kind of cell that is frequently observed in the bronchoalveolar lavage (BAL) fluid of individuals with diffuse alveolar damage (DAD). Because of their exposure to iron in the BAL fluid, these macrophages are loaded with haemosiderin. These cells, which are not frequently observed in normal lungs, are a reliable sign of DAD. Haemosiderin-stained macrophages may be seen with the use of specialized dyes and are frequently used to diagnose DAD.

14th Apr 2022 Sean Mac Fhearraigh PhD

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