M2 macrophages are not a homogeneous population, but rather a heterogeneous group of subtypes with distinct phenotypes and functions. The four main subtypes of M2 macrophages are M2a, M2b, M2c, and M2d. Each subtype has its own stimuli, surface markers, cytokine profiles, signaling pathways, and roles in diseases.

Creative Biolabs summarizes the subtypes, functions, and diseases associated with M2 macrophages.

Phenotypes of M2 Macrophages

M2 macrophages are a heterogeneous group of macrophages that exhibit anti-inflammatory, tissue remodeling, immune regulatory, and tumor promoting activities. They are generally characterized by their high expression of mannose receptor (CD206), scavenger receptor (CD163), arginase 1 (Arg1), and interleukin-10 (IL-10). However, M2 macrophage functional phenotypes can be further divided into four subtypes: M2a, M2b, M2c, and M2d, based on their different stimuli, markers, cytokines, and functions.

Table 1. Comparison of four subtypes of M2 macrophages.

The four subtypes of M2 macrophages share some common features, such as their anti-inflammatory properties, their ability to modulate adaptive immunity, and their involvement in tissue remodeling. However, they also have distinct features that reflect their specific stimuli, markers, cytokines, and functions. Therefore, it is important to recognize the diversity and complexity of M2 macrophages in different physiological and pathological conditions.

M2 Macrophage Functions

M2 macrophages have several functions that are relevant to inflammatory immune skin diseases. By leveraging our expertise in macrophage characterization, you have access to complete, high-quality functional information on M2.

• Tissue Repair and Wound Healing
  • M2 macrophages promote tissue repair and wound healing by secreting growth factors that stimulate angiogenesis, fibroblast proliferation, and collagen synthesis.
  • M2 macrophages secrete anti-inflammatory cytokines that suppress inflammation and fibrosis.
  • M2 macrophages phagocytose apoptotic cells and debris, and facilitate the clearance of pathogens and damaged tissue.
• Immune Regulation
  • M2 macrophages modulate the immune response by interacting with other immune cells, such as T cells, B cells, dendritic cells, mast cells, and eosinophils.
  • M2 macrophages induce Th2 differentiation and activation by secreting IL-4 and IL-13, or inhibit Th1 and Th17 differentiation and activation by secreting IL-10 and TGF-β.
  • M2 macrophages activate B cells and antibody production by expressing CD23 and CD86. They can also suppress the activation of dendritic cells by expressing CD200R and PD-L1.
  • M2 macrophages recruit and activate mast cells and eosinophils by secreting chemokines, such as CCL17, CCL18, CCL22, and CCL24.
• Tumor Promotion
  • M2 macrophages promote tumor growth and metastasis by creating a favorable microenvironment for cancer cells. They secrete pro-angiogenic factors that enhance tumor vascularization.
  • M2 macrophages secrete anti-inflammatory cytokines that inhibit anti-tumor immunity.
  • M2 macrophages secrete matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) that degrade the extracellular matrix and facilitate tumor invasion.
  • M2 macrophages express scavenger receptors that uptake tumor-derived factors.
• Macrophage Phagocytosis
  • M2 macrophages express high levels of scavenger receptors that bind to various ligands.
  • M2 macrophages express high levels of Fc receptors that mediate antibody-dependent cellular phagocytosis (ADCP) of opsonized targets.

M2 Macrophage in Diseases

M2 macrophages are involved in various diseases, such as

• Inflammatory Immune Skin Diseases
• Chronic Allograft Rejection
• Cancer
• Obesity
• Diabetes

M2 macrophages are important immune cells that can be modulated or targeted for disease treatment, especially cancer. Several strategies have been developed or proposed to manipulate M2 macrophages, such as reprogramming, depletion, inhibition, or delivery of M2 macrophages.

• M2 macrophages reprogramming means converting their pro-tumoral and anti-inflammatory phenotype into an anti-tumoral and pro-inflammatory phenotype. This can be done by using agents or stimuli that can induce M2 to M1 repolarization and enhance the anti-tumor activity of macrophages.
• Depletion of M2 macrophages means reducing or eliminating their number or density in the tumor microenvironment. This can be done by using agents or strategies that can selectively bind and deplete M2 macrophages, such as antibodies, small molecules, bispecific T cell engagers, or chimeric antigen receptor (CAR) T cells.
• Inhibition of M2 macrophages means blocking or suppressing their function or activity in the tumor microenvironment. This can be done by using agents or strategies that can inhibit the production of immunosuppressive mediators by M2 macrophages, such as small molecules, peptides, antibodies, microRNAs, or nanoparticles.
• Delivery of M2 macrophages means using M2 macrophages as vehicles or carriers to deliver therapeutic agents or payloads to the tumor site. This can be done by using agents or strategies that can exploit the homing, phagocytic, migratory, and infiltrative abilities of M2 macrophages, such as drugs, genes, proteins, nanoparticles, or cells.

In summary, targeting M2 macrophages is a novel and promising therapeutic strategy for various diseases. However, there are still some challenges and limitations that need to be addressed, such as the specificity, safety, efficacy, and delivery of the agents or strategies that target M2 macrophages. Further research and development are needed to optimize and improve the therapeutic applications of M2 macrophages.

References

1. Yunna C, et al. "Macrophage M1/M2 polarization". Eur J Pharmacol, (2020).
2. Zhang H, et al. "M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection". Front Immunol, (2021).