What Are They, Different Types, Function, and More

Author: Lily Guo

Editors: Alyssa Haag, Ian Mannarino, MD, MBA, Kelsey LaFayette, DNP, RN

Illustrator: Abbey Richard

Copyeditor: Sadia Zaman, MBBS, BSc

What are macrophages?

Macrophages are a type of white blood cell that play an important role in the human immune system and carry out various functions including engulfing and digesting microorganisms; clearing out debris and dead cells; and stimulating other cells involved in immune function. Macrophages confer innate immunity, which is typically the first line of defense against foreign antigens. Adaptive immunity, on the other hand, is the subtype of the immune system that involves specialized immune cells and antibodies. In addition to having an immune role, macrophages also secrete anti-inflammatory cytokines (i.e., small signaling proteins) and help mediate reparative processes. 

Macrophages form from monocytes, which themselves derive from the bone marrow. Monocytes circulate through the blood for one to three days before migrating into tissues, where they become macrophages or dendritic cells (i.e., a type of antigen presenting cell that plays a role in linking the innate and adaptive immunity). Macrophages can be found within many organs in the body, including the liver, brain, bones, and lungs, as well as in the blood, particularly at sites of infection.

Two illustrated macrophages, one in the first step of phagocytosis the other completing phagocytosis by engulfing and removing a pathogen.

What are the types of macrophages?

Macrophages can largely be categorized into two main types: M1 and M2 macrophages. The M1 type, referred to as classically-activated macrophages, are activated by pathogen invasion and play a large role in the immune response to foreign pathogens such as bacteria. The M2 type, referred to as alternatively-activated macrophages, play a role in wound healing and tissue repair, and have an anti-inflammatory role. 

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What is the function of macrophages?

Generally, macrophages play a role in destroying infectious organisms that enter the body, clearing cellular debris, and wound healing. They also play an important role in forming granulomas, which are aggregations of macrophages that function in walling off an infection. The specific function of M1 macrophages is to detect, engulf and destroy bacteria. They can do this through phagocytosis, which is a process by which a bridge is formed between cellular receptors on the macrophage and surface antigens on the bacteria. Once the bridge is formed, the membrane of the macrophage protrudes out and surrounds the bacteria. Once inside the macrophage, the bacteria is trapped within a phagosome, or a vesicle, which then fuses with a lysosome. The lysosome contains enzymes and peroxides that are able to digest the pathogen. M1 macrophages promote inflammation; extracellular matrix (ECM) destruction; apoptosis of invading cells by releasing various cytokines and nitric oxide to aid in cellular destruction; and antigen presentation, making them antigen-presenting cells (APCs). After a macrophage processes and digests the antigen, a major histocompatibility complex (MHC) molecule delivers the antigen to the surface of the macrophage to allow a T-cell receptor to bind. This triggers the adaptive immune response of our body to recognize the foreign antigen and mount further mechanisms to kill the cells. 

M2 macrophages on the other hand are needed for regeneration of connective tissue during wound healing. They produce vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β1 which allows for vascular stability and wound repair. M2 macrophages also function to phagocytize bacteria and damaged tissue around the wound. They are then able to debride damaged tissue by releasing digestive enzymes such as proteases, which are enzymes that break down protein. Subsequently, they secrete growth factors, stimulate cells to re-epithelialize the wound, create granulation tissue, and lay down a new extracellular matrix. 

Macrophages play additional roles within specific organ systems. For example, as air is inhaled into the lungs for oxygen exchange, toxic substances (e.g., bacteria, viruses, and fungi) may be taken into the lungs, specifically, the alveoli (i.e., air sacs of the lung). Lung macrophages are able to process bacteria and other toxic substances in the alveoli to prevent diseases such as tuberculosis via formation of granulomas. Within the liver, macrophages are given the specific name of Kupffer cells. Kupffer cells scavenge the liver for potential pathogens that could have entered the bloodstream from the gastrointestinal tract. They also play a role in maintaining iron levels and have a function in bilirubin metabolism. If the liver is injured, Kupffer cells secrete anti-inflammatory cytokines (e.g., Interleukin [IL]-10, IL-4, and IL-13). Macrophages of the brain are called microglia. Microglia have a neuroprotective effect and secrete various anti-inflammatory cytokines and nerve injury factors. If neurons are damaged, microglia are recruited to the site, and can phagocytose dead cells and foreign materials to prevent further tissue damage.

Are macrophages good or bad?

Overall, macrophages are good and play a critical role in the human body. They protect our body from bacterial and viral infections by secreting antimicrobial mediators and pro-inflammatory cytokines, while also mediating repair through an anti-inflammatory response. They also allow for protection from neuronal damage in the brain, and regulate iron and bilirubin levels in the liver. 

There are some pathological effects of macrophages, however. For example, a type of M2 macrophage, the tumor-associated macrophage (TAM), promotes tumor growth via suppression of the immune system. Therapies are currently being developed to target TAMs. Additionally, both M1 and M2 macrophage populations play a role in promotion of atherosclerosis, which is an arterial disease characterized by fatty deposition on the vessel walls. M1 macrophages cause inflammation of the vessels, whereas M2 macrophages remove cholesterol from blood vessels, which then become oxidized and transformed into atheromatous plaques. Hypertension and cardiovascular disease can be consequences of this process. 

What are the most important facts to know about macrophages?

Macrophages are a type of white blood cell that play an integral part in the  immune system with the role of phagocytosing foreign antigens, such as bacteria. They are able to present these antigens to other immune cells, such as T-cells, for further destruction. Macrophages also play a role in wound healing and tissue repair. They attract anti-inflammatory cytokines, which mediate vascular growth and have microcidal properties, to the wound site. Macrophages have very positive effects and maintain tissue homeostasis within humans, however they can also contribute to disease. This can be the case when tumor-associated macrophages evade suppression by the immune system and promote tumor growth, or when atherosclerosis is promoted within arteries by the action of macrophages. 

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Related links

Innate immune system
T-cell activation

Resources for research and reference

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Lin, Y., Xu, J., & Lan, H. (2019). Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications. Journal of Hematology & Oncology, 12(1): 76. DOI: 10.1186/s13045-019-0760-3 

Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M. (2000). M-1/M-2 macrophages and the th1/th2 paradigm. The Journal of Immunology, 164(12): 6166–6173. DOI: 10.4049/jimmunol.164.12.6166 

Ovchinnikov, D. A. (2008). Macrophages in the embryo and beyond: much more than just giant phagocytes. Genesis, 46(9): 447–62. DOI: 10.1002/dvg.20417

Willekens, F. L., Werre, J. M., Kruijt, J. K., Roerdinkholder-Stoelwinder, B., Groenen-Döpp, Y. A., van den Bos, A. G., Bosman, G. J., & van Berkel, T. J. (2005). Liver Kupffer cells rapidly remove red blood cell–derived vesicles from the circulation by scavenger receptors. Blood, 105(5): 2141–2145. DOI: 10.1182/blood-2004-04-1578