A Guide to Macrophage Markers

Macrophages are a versatile and widely distributed type of white blood cell found in many, if not all, tissues of the body. A part of the mononuclear phagocyte system, their defining role is to engulf dead cells, cellular debris, pathogens, and other foreign objects. They also possess signaling and regulatory functions, allowing them to be entrenched deeply in many biological pathways, including immunity, development, repair, homeostasis, and cancer. This complex role highlights the importance of observing the abundance and function of macrophages in various biological environments. In this guide, we provide a broad overview of genes expressed by macrophages, along with immunological tools for detection. Targeting these proteins is useful not only for identifying macrophage subtypes, but also in studying related pathways or disease states.

Grouping macrophage markers

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In addition to diverse tissue-specific roles, macrophages are highly plastic and are capable of altering their phenotype in response to environmental signals. This results in fundamentally distinct subpopulations of macrophage types, each with varying gene expression profiles and cellular functions. To better understand these differences, it may help to categorize protein markers according to these contexts.

Markers in the monocyte-macrophage transition

Macrophages can originate from embryonic precursors and from bone marrow-derived monocytes. These monocytes, which circulate in the bloodstream, differentiate into macrophages upon migrating into tissues or during an immune response. This closely related cell type effectively serves as a reservoir for replenishing populations of tissue macrophages. To distinguish monocyte-derived macrophages from their precursors, it is common to detect a set of cell surface markers along with their differential expression levels.

Examples of antibodies for monocyte lineage markers: Ly6c1 antibodies, F4/80 antibodies, ITGAM/CD11b antibodies, CD68 antibodies, FCGR3A/CD16 antibodies, CD14 antibodies

Figure 1. A broad overview of the macrophage cell development lineage that gives rise to various macrophage subtypes.

Markers for tissue-specific subtypes

Macrophages reside within different tissues, resulting in diverse cell populations that perform tissue-specific and niche-specific functions. For instance, macrophages that develop in the central nervous system, known as microglia, have been found to carry out multiple roles, including scavenging debris, remodeling synaptic connections, and immune surveillance. In adipose tissue, adipose-associated macrophages participate in signaling that regulates insulin sensitivity. Lung alveolar macrophages attack inhaled foreign agents and also clear excess pulmonary surfactants by phagocytosis. Kupffer cells, or stellate macrophages in the liver, work in clearing the blood of microorganisms, red blood cells, and other cell debris. Bone marrow macrophages promote red blood cell hematopoiesis by engulfing extruding nuclei of developing erythrocytes. Macrophages in the spleen, including marginal zone, metallophilic, red pulp, and white pulp macrophages, engage in activities such as immune surveillance, iron metabolism, and cell clearance. 

Examples of antibodies for tissue macrophage markers: CD68 antibodies, MARCO antibodies, MRC1/CD206 antibodies, PPARG antibodies, CD80 antibodies, CD11c antibodies

Markers for M1 and M2 polarization

Given appropriate stimuli, macrophages are provoked and activated into a type of inflammatory state, which can be broadly grouped into either of two classes, M1 (classically activated) or M2 (alternatively activated). This nature of polarization represents opposite ends of a spectrum and refers only to an estimate of activation at a given point in time and location. M1 macrophages have been described to have a pro-inflammatory role associated with immune responses to bacteria and intracellular pathogens. On the other hand, M2 has been associated with a more anti-inflammatory role, with functions in angiogenesis and wound healing. M2 is also associated with T helper type 2 (Th2) responses, such as helminth immunity, asthma, and allergy.

M1 macrophage activation occurs through signaling by IFNG, TNF, and toll-like receptors. Genetic markers associated with M1 polarization include IL1a, IL1b, IL6, NOS2, TLR2, TLR4, CD80, and CD86. For M2 macrophages, activation occurs through cytokines including IL4, IL10, and IL13. Reported M2 markers include CD115, CD206, PPARG, ARG1, CD163, CD301, Dectin-1, PDL2, and Fizz1. It is important to note that due to the continuum of phenotypes between M1 and M2, macrophages that fall in the middle range can express some markers simultaneously.

Examples of antibodies for M1 markers: IL1B antibodies, NOS2 antibodies, TLR2 antibodies, CD86 antibodies; M2 markers: CSF1R/CD115 antibodies, MRC1/CD206 antibodies, ARG1 antibodies, CD163 antibodies 

Markers for tumor-associated macrophages

Cancer cells are known to exploit macrophage processes in order to promote cancer progression. In the clinical setting, an increased density of macrophages in tumor sites has been correlated with poor patient survival in many types of cancer. Studies in mice have found that tumor-associated macrophages (TAMs) can stimulate tumor angiogenesis, assist with tumor cell migration and invasion, and suppress tumor immunity. These outcomes arise in part due to cancer cell signaling that influences macrophage function, as well as the production of proteins by TAMs themselves to promote tumor growth. The nature of cancer biology is complex, and similarly, TAMs can adopt distinct and diverse gene expression profiles. Some TAM markers mentioned in the literature include CCR2, CSF1R, MARCO, PDL2, CD40, CCL2, CSF1, CD16 and PDGF beta. The close relationship between macrophages in cancer continues to be an active area in research and drug development.

Examples of antibodies for TAM markers: CCR2 antibodies, PDL2 antibodies, CD40 antibodies, CCL2 antibodies, PDGFB antibodies

Table of macrophage markers

The following table provides a broad list of proteins expressed by macrophages, as mentioned by various sources. They are categorized by their human NCBI gene symbol (Gene), common names (Synonyms), expression in human or mouse (Species), type of macrophage marker (Marker Type), protein type, cellular localization, and protein size. For each marker, a link is provided to listings of relevant antibodies and ELISA kits. These immunological tools are commonly used for investigating specific cell types and their markers via flow cytometry, staining by IF, IHC or ICC, and by immunoassay. The listings are sourced by an assortment of reagent suppliers, providing an extensive pool of products from which to compare and choose.

* MHC class II is a multi-subunit protein complex composed of several distinct genes. Information on Protein Type, Localization, and Size (kDa) obtained from UniProt.org. 

References:
1. Wynn, Thomas A., et al. “Macrophage Biology in Development, Homeostasis and Disease.” Nature, vol. 496, no. 7446, Apr. 2013, pp. 445–55. doi:10.1038/nature12034.
2. Murray, Peter J. “Macrophage Polarization.” Annual Review of Physiology, vol. 79, no. 1, Feb. 2017, pp. 541–66. doi:10.1146/annurev-physiol-022516-034339.
3. Gentek, Rebecca, et al. “Tissue Macrophage Identity and Self-Renewal.” Immunological Reviews, vol. 262, no. 1, Nov. 2014, pp. 56–73. doi:10.1111/imr.12224.
4. Davies, Luke C., et al. “Tissue-Resident Macrophages.” Nature Immunology, vol. 14, no. 10, Oct. 2013, pp. 986–95. doi:10.1038/ni.2705.
5. Cassetta, Luca, and Jeffrey W. Pollard. “Targeting Macrophages: Therapeutic Approaches in Cancer.” Nature Reviews Drug Discovery, vol. 17, no. 12, Dec. 2018, pp. 887–904. doi:10.1038/nrd.2018.169.
6. Varol, Chen, et al. “Macrophages: Development and Tissue Specialization.” Annual Review of Immunology, vol. 33, no. 1, Mar. 2015, pp. 643–75. doi:10.1146/annurev-immunol-032414-112220.
7. Taylor, P. R., et al. “MACROPHAGE RECEPTORS AND IMMUNE RECOGNITION.” Annual Review of Immunology, vol. 23, no. 1, Apr. 2005, pp. 901–44. doi:10.1146/annurev.immunol.23.021704.115816.
8. Hesketh, Mark, et al. “Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing.” International Journal of Molecular Sciences, vol. 18, no. 7, July 2017, p. 1545. doi:10.3390/ijms18071545.
9. Tissue:Macrophage AND Organism:"Homo Sapiens (Human) [9606]" in UniProtKB. https://www.uniprot.org/uniprot/?query=tissue:macrophage&fil=organism%3A%22Homo+sapiens+%28Human%29+%5B9606%5D%22&sort=score. Accessed 20 July 2020.
10. CellMarker. http://biocc.hrbmu.edu.cn/CellMarker/search.jsp?quickSearchInfo=macrophage. Accessed 20 July 2020.