Monocytes and Macrophages: Macrophage and Monocyte Function, Origin and Related Conditions

We rely on the components of our adaptive and innate immune systems working in conjunction to prevent disease, allow correct development, renew and repair when needed and keep our body systems functioning correctly.

What are monocytes and what are macrophages?

Monocytes and macrophages are types of white blood cell, specifically leukocytes or mononuclear phagocytes. They are part of the innate immune system that provides the front line of defense against invading microorganisms and foreign particles. They were first described by the Russian physician Élie Metchnikoff in 1882, for which he was awarded the Nobel prize, along with Paul Ehrlich, in 1908.^1,2

The majority are derived from bone marrow-located hematopoietic stem cells, which must first differentiate into common myeloid progenitor cells and then subsequently into granulocyte–macrophage progenitors. This cell type can either become a granulocyte progenitor (then eventually a basophil, neutrophil or eosinophil), or, via a monoblast and then a promonocyte, a monocyte and subsequently a macrophage (Figure 1).

Both monocytes and their subsequently differentiated macrophages are large and agranular with a relatively clear cytoplasm. Monocytes have a kidney shaped nucleus, which is more irregular in macrophages.³ Macrophages are typically amoeboid in shape and have an abundant cytoplasm that may contain vacuoles or phagocytic vessels. Once released from the bone marrow into the bloodstream, circulating monocytes generally live for only a couple of days and account for approximately 2–8% of circulating white blood cells.⁴ Once differentiated, macrophages may live for months in tissue locations.⁵

It is important to note that certain macrophages do not develop from monocytes, instead being derived from embryonic progenitors, for example Kupffer cells in the liver, and are often described as tissue-resident macrophages.⁶

Figure 1: Diagram showing the differentiation pathway for the development of monocytes and macrophages. Credit: Technology Networks.

Monocyte and macrophage functions

Monocyte function

The primary function of monocytes was considered historically to be to act as a pool of cells that sensed the environment and replenished the pool of tissue located macrophages and dendritic cells (DCs). More recently, however, it has been determined that they are highly heterogeneous and serve multiple functions. Three primary populations are distinguished by their function in homeostasis and disease and by the expression of surface markers as, summarized in Table 1.^7,8,9

Table 1: A comparison of the different types of monocyte.

Macrophage function

Probably the first idea about the function of macrophages that comes to mind is their involvement in the innate immune response and the process of phagocytosis. They are highly effective at recognizing, engulfing and digesting bacteria, viruses and dead cells, thus removing them from the body.¹⁰

However, it has become increasingly clear that they are a highly heterogeneous population of cells that play a much more wide ranging role in the adaptive immune response, development and multiple homeostatic functions.

Macrophages produce and release various cytokines that can stimulate inflammation, recruiting other cell types including monocytes, neutrophils, endothelial cells, T cells, DCs, mast cells and fibroblasts to the site of infection or injury, and modulate the activity of nearby cells.¹¹ Additionally, they are capable of processing antigens and presenting them to other immune cells, such as T cells. This process is essential for activating the adaptive immune response and initiating an appropriate immune reaction against pathogens.¹²

Continue reading below...

Looking for content on The Immune System?

Visit this Topic Page to find a variety of curated content on The Immune System.

Visit Topic Page

They play a crucial role in regulating immune responses to maintain immune homeostasis and prevent excessive inflammation or immune-mediated tissue damage. Both pro-inflammatory and anti-inflammatory effects are instigated by macrophages depending on the context of the immune response.

Other homeostatic functions that have been attributed to macrophages include maintaining constant levels of iron, bilirubin, calcium, lipids and amino acids.¹³ Macrophages are also involved in tissue remodeling and repair processes following injury or infection. They clear debris, produce growth factors that stimulate cell proliferation and tissue regeneration and orchestrate the resolution of inflammation.¹⁴

Finally, they contribute in a number ways to the development of various systems, being involved in embryogenesis and organogenesis, including the immune system, the neural system and the vascular system as well as in bone development and remodeling, tissue remodeling and homeostasis.¹⁵

Monocyte vs macrophage

Table 2 summarizes the key features of monocytes and macrophages.

Table 2: A comparison of monocytes and macrophages.

What does absolute monocytes mean?

Absolute monocytes, also known as the absolute monocyte count, refers to the number of monocytes present in a given volume of blood, normally per microliter or milliliter. It is typically measured as part of a complete blood count (CBC) test, which provides information about the cellular components of blood and disease status. Normal levels are between 0.2–0.8 × 10⁹/L.¹⁶

Conditions related to monocytes and macrophages

Changes in monocyte and macrophage function can be associated with various diseases. Some diseases linked to increased or decreased levels of each cell type or to abnormalities in function are discussed below.

Conditions that cause elevated levels of monocytes (monocytosis)¹⁶

1. Bacterial, viral, fungal or parasitic infections can lead to an increase in monocytes as part of the immune response. It is often associated with subacute or chronic infections such as tuberculosis, brucellosis, syphilis and trypanosomiasis.
2. Chronic inflammatory autoimmune conditions like rheumatoid arthritis, inflammatory bowel disease (IBD) and systemic lupus erythematosus can cause monocytosis due to immune dysregulation.
3. Sarcoidosis can lead to the formation of granulomas in various organs and elevated levels of monocytes.
4. Certain cancers can lead to an elevated monocyte count; these include acute monocytic or myelomonocytic leukemia, chronic myelomonocytic leukemia and a wide variety of myeloid neoplasms.
5. Monocytosis can be associated with some myelodysplastic syndromes that are characterized by abnormal development and function of blood cells in the bone marrow.
6. Certain drugs may also cause monocytosis, such as ampicillin and tetrachloroethane.

Conditions associated with decreased levels of monocytes (monocytopenia)¹⁷

Monocytopenia is less common that monocytosis but can be associated with a variety of causes, including, aplastic anemia, myelodysplastic syndromes, severe infection due to monocyte recruitment to the site of infection, some nutritional deficiencies (folate) and cancer therapies including chemotherapy and radiotherapy. Some rare congenital disorders like MonoMAC syndrome, caused by mutation in the GATA-2 gene, can lead to severe monocytopenia.

Conditions related to macrophages

1. Macrophage activation syndrome (MAS): MAS is a severe, life-threatening complication of some autoimmune diseases, such as systemic juvenile idiopathic arthritis where an uncontrolled activation and proliferation of macrophages leads to widespread inflammation.¹⁸
2. Hemophagocytic lymphohistiocytosis (HLH): This life threatening, rare and aggressive disorder is characterized by excessive activation of macrophages and cytotoxic T cells, leading to hyperinflammation. It can be genetic or acquired and may be associated with infections, autoimmune diseases or malignancies.¹⁹
3. Langerhans cell histiocytosis (LCH): LCH is an idiopathic condition associated with the proliferation of Langerhans cells that can lead to tissue damage throughout the body, including the liver, spleen, bone marrow and eyes.²⁰
4. Sarcoidosis: This complex, idiopathic, condition is associated with the accumulation of both activated lymphocytes and macrophages, leading to granulomas throughout the body. It is not normally life threatening but can become chronic.²¹
5. Tumor-associated macrophages (TAMS): Macrophages are capable of infiltrating tumors and, depending upon the subtype, can have both tumor suppressing activity or can promote occurrence, induce metastasis and prevent anti-tumor responses.²²
6. Chronic inflammatory conditions: Rheumatoid arthritis, systemic lupus erythematosus and IBDs involve chronic inflammation where macrophages are actively participating.²³ They are also involved in the pathology of atherosclerosis.²⁴
7. Infections: Infection by certain pathogens can lead to modifications in macrophage function. For example, the human immunodeficiency virus (HIV) infects and affects macrophages, contributing to immune system dysfunction.²⁵
8. Niemann-Pick disease (NP): NP refers to a rare group of autosomal recessive metabolic disorders where there is an accumulation of lipids in lysosomes. It is associated with either breakdown or transport of sphingolipids, depending on the type of mutation causing the disease, and causes an accumulation of sphingomyelin in the monocyte/macrophage phagocyte lineage. Clinical signs of disease vary depending upon the type of NP, but include enlargement of the liver and spleen, thrombocytopenia, bone and neurological issues.²⁶
9. Gaucher’s disease (GD):²⁷ GD is a group of rare, autosomal recessive diseases associated with mutations in the glucocerebrosidase enzyme, leading to accumulation of glucosylceramide in macrophages, known as Gaucher cells. These cells can infiltrate and accumulate in various tissues, causing enlargement of the liver and the spleen, displacement of bone marrow, bleeding, skeletal alterations and thrombocytopenia. It has also been associated with Parkinson’s disease.²⁸

Historically both monocytes and macrophages were considered to be homogeneous populations of leukocytes tasked with removing invading bodies from our systems. However, more recent data has shed light on the heterogeneity of both monocytes and macrophages, their multiple roles in the innate and adaptive immune responses and multiple homeostatic functions.