Macrophages are highly plastic and adaptable, and can change their phenotype and function in response to different stimuli. Macrophage phenotypes are defined by the expression of specific surface markers, cytokines, enzymes, and receptors, as well as by the metabolic and epigenetic profiles of the cells. The main macrophage phenotypes that have been described are M1 and M2, which represent the two extremes of a spectrum of functional states. However, these phenotypes are not mutually exclusive, and macrophages can also display intermediate or mixed features depending on the context.

Creative Biolabs provides an overview of the current knowledge on macrophage phenotypes and their regulation by various microenvironmental factors.

M1 Macrophages

Classically activated m1 macrophages exhibit pro-inflammatory, microbicidal, and immunostimulatory activities. M1 macrophages are characterized by the expression of high levels of pro-inflammatory cytokines. They also produce high amounts of nitric oxide (NO) and reactive oxygen species (ROS). Furthermore, M1 macrophages express high levels of major histocompatibility complex class II (MHC-II) molecules and co-stimulatory molecules.

• The activation of M1 macrophages is mainly regulated by Th1 cytokines or microbial products.
• The biological functions of M1 macrophages are essential for host defense against intracellular pathogens.
  • M1 macrophages can phagocytose and destroy these pathogens by producing NO and ROS, which disrupt their membranes and DNA.
  • M1 macrophages can also secrete cytokines that activate other immune cells.
  • Moreover, M1 macrophages can present antigens to T cells and initiate adaptive immune responses that confer long-term protection against reinfection.

Fig.1 Pathways of inflammation in M1 macrophages.¹

• The pathological implications of M1 macrophages are also evident in chronic inflammation, tissue damage, autoimmune diseases, and cancer.

M2 Macrophages

Alternatively activated m2 macrophages exhibit anti-inflammatory, tissue remodeling, and immunoregulatory activities. M2 macrophages are characterized by the expression of low levels of pro-inflammatory cytokines and high levels of anti-inflammatory cytokines. They also produce high amounts of arginase, which converts L-arginine to ornithine and urea, and is involved in wound healing and fibrosis. Furthermore, M2 macrophages express high levels of scavenger receptors, which enable them to clear debris and apoptotic cells.

• The activation of M2 macrophages is mainly regulated by Th2 cytokines or anti-inflammatory mediators. Some epigenetic modifications, such as histone methylation and acetylation, also modulate the expression of M2-related genes.
• The biological functions of M2 macrophages are essential for wound healing, tissue repair, angiogenesis, fibrosis, and parasite clearance.
  • M2 macrophages can promote wound healing by producing arginase, which stimulates collagen synthesis and extracellular matrix deposition.
  • M2 macrophages can also facilitate tissue repair by producing growth factors, which stimulate angiogenesis and cell proliferation.
  • M2 macrophages can clear parasites by producing eosinophil-attracting chemokines, which recruit eosinophils that have cytotoxic effects on parasites.

Fig.2 M2-like tumor-associated macrophages promote angiogenesis, lymphangiogenesis, immunosuppression, and tumor metastasis.²

• The pathological implications of M2 macrophages are also evident in allergic inflammation, chronic infection, tumor progression, and metabolic disorders.

Other Types and Sub-types of Macrophages

Macrophages can display a variety of intermediate or mixed phenotypes that are influenced by multiple and dynamic signals in the microenvironment. Moreover, macrophages can also acquire tissue-specific or disease-specific functions that are not easily classified into M1 or M2 categories. Therefore, several other types and sub-types of macrophages have been identified and characterized by different researchers.

Table 1. Macrophage phenotypes induced by different stimuli

In conclusion, macrophages have different phenotypes and functions depending on the signals they receive from their microenvironment. Creative Biolabs provides a variety of macrophage markers and other cellular markers to help researchers identify and analyze macrophage function and phenotype.

References

1. Lyons, Claire L., Elaine B. Kennedy, and Helen M. Roche. "Metabolic inflammation-differential modulation by dietary constituents." Nutrients 8.5 (2016): 247.
2. Gao, Jing, Yuanzheng Liang, and Liang Wang. "Shaping polarization of tumor-associated macrophages in cancer immunotherapy." Frontiers in Immunology 13 (2022): 888713.