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The Marvellous Multi-faceted Macrophages

Macrophages in a tissue culture dish

Macrophages in a tissue culture dish

What can macrophages do?

Most people know about the cleaning capabilities of macrophages but there is much more to macrophages than this.  Albeit, macrophages do ‘eat’ dead or damaged cells but what is not commonly known is that they do not just dissolve their ‘meal’, they  process their meal and then present it to T cells (another type of white blood cell) to show them the enemy for future reference. Macrophages also release signals calling for back up from other white blood cells. This, in general terms, is known as the inflammatory response. Macrophages also release toxic chemicals during inflammation, thereby destroying nearby tissues as well as the infecting pathogens (disease-causing organisms). These chemicals are oxidants: reactive oxygen species and nitric oxide. The very same oxidants health magazines warn people about and tell us we need to eat more anti-oxidants to counter.

They are also involved in the wounding-healing process and in the formation of blood vessels, both during ordinary foetal development and, then later in life, during disease (for example, in cancer). During the wound healing process, macrophages are the key regulators of repair, and involved in scar tissue (fibrosis) formation. They are in close contact with blood vessels during both development and during diseases such as wet age-related macular degeneration. Upon activation by cancer cells, macrophages release a variety of different types of proteins, many of which are important in cancer metastasis (spreading of cancer). The presence of a certain type of macrophage – tumour associated macrophage (i.e. TAM) correlates with poor prognosis in a variety of cancer types.

Macrophages play a pivotal role in diseases associated with low level chronic inflammation such as during cardiovascular disease, diabetes and cancer. These conditions have one thing in common – obesity. Obesity-induced chronic inflammation increases their risk. Recently, macrophages have been found in the fat around internal organs (known as visceral fat). The types of macrophages within the viscersal fat of a lean person and an obese person are different (the two types of macrophages are M1 and M2, more on this below). Fatty tissue sends signals (chemokines) to recruit and retain macrophages and these macrophages have a role in chronic inflammation and insulin resistance leading to type II diabetes.

Macrophages play a key role during cardiovascular disease. They are present in clogged arteries (atherosclerosis) within the plaques, affecting their stability where they ‘eat’ (phagocytosis) the lipoproteins. Once engorged, they turn into cholesterol-laden foam cells.  These macrophages seem unable to leave the plaque. They make inflammatory proteins, degrade their surrounding structures (by producing matrix-degrading proteases) which thin the cap on the plaque and eventually die. These dead cells make up the necrotic core of the plaque and contribute to its rupture. Unstable plaques are causal of myocardial infarction and stroke.

How do macrophages do this?

Courtesy of Dr. Volker Brinkmann, Max Planck Institute for Infection Biology, Berlin/ Germany

Macrophages act differently depending on their environment. When they are involved in inflammation, they are pro-inflammatory (also known as M1) but when they are involved in wound healing they are regulatory (also known as alternatively activated or M2). The macrophage behaviour depends on which signalling molecules are present in the tissue or organ. Some signalling molecules make macrophages into M1 while others make them into M2. One example of a signalling molecule (cytokine) that can make macrophages inflammatory is called tumour necrosis factor (TNF). Without TNF to activate them, macrophages cannot get rid of infections such as TB. When things go wrong and the immune system starts attacking the body (autoimmune disease) as in rheumatoid arthritis, Crohn’s and non-infectious uveitis (a disease affecting the eye and eventually leading to blindness), TNF is the culprit.

Other signalling molecules, such as IL-4 and TGFβ1, make them into M2 macrophages. M2 macrophages form scar tissue and produce a protein called VEGF that sends a signal to blood vessels encouraging them to make branches and more blood vessels. These macrophages turn off the inflammatory response.

These macrophage subsets are not distinct, there is overlap and macrophages can change their function depending on their environment.

Where do macrophages come from?

Monocytes and macrophages are very similar. Monocytes are formed in the bone marrow and then enter the blood stream. They circulate around the body in the blood until they are needed within a particular organ or tissue. These tissues make and secrete signalling molecules (known as cytokines or chemokines) which attract cells in from the blood. Once these monocytes leave the blood and enter tissues or organs, they turn into macrophages. These macrophages have different names depending upon which organ they are in. For example, in the kidneys they are called mesangial cells and in the eyes and brain they are called microglia.

The ratios of different types of macrophages vary in healthy and ill people and mice. Illness includes people with an infection, autoimmune disease, cardiovascular disease and obese people.

Here is a (short) list of future offerings:

  • Macrophages and fat tissue
  • Atherosclerosis
  • The importance of TNF
  • Age-related macular degeneration

Tarnjit Khera (2014). The Marvellous Multi-faceted Macrophages
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