Other Types and Sub-types

Besides M1 and M2, there are other types and subtypes of macrophages that have been identified and characterized in various conditions, such as M3, Mres, Mreg, M(Hb), M(IL-10) and TAMs. These macrophages have distinct features and functions, and play important roles in health and disease.

Creative Biolabs provides a review of several other types and sub-types of macrophages including M3, Mres, Mreg, M(Hb), M(IL-10) and TAMs.

M3 Macrophages

M3 macrophages are a type of anti-inflammatory macrophages that are induced by IL-4 and IL-10. M3 macrophages have a phenotype that is similar to M2 macrophage functional phenotypes, but with some differences, such as higher expression of CD163 and lower expression of CD206.

M3 macrophages have a function that is mainly anti-inflammatory, wound healing and tissue remodeling. They can suppress the production of pro-inflammatory cytokines, such as TNF-α and IL-6, and enhance the production of anti-inflammatory cytokines, such as IL-10 and TGF-β.
M3 macrophages have a role in disease that is mainly anti-tumoral. They can inhibit tumor growth and metastasis by inducing apoptosis, cytotoxicity and immune modulation. For example, M3 macrophages can kill melanoma cells by producing nitric oxide.

Fig.1 The hypothesis of the existence of the M3 phenotype: the switching phenotype.¹

Mres Macrophages

Mres macrophages are a type of highly phagocytic and bactericidal macrophages that are induced by IFN-γ and GM-CSF. Mres macrophages have a phenotype that is similar to M1 macrophage functional phenotypes, but with some differences, such as higher expression of CD64 and lower expression of CD86.

Mres macrophages have a function that is mainly macrophage phagocytosis, killing and antiviral. They can engulf and destroy various pathogens, such as bacteria, fungi and viruses, and produce reactive oxygen species and nitric oxide.
Mres macrophages have a role in disease that is mainly clearance of infection and inflammation. They can eliminate the infectious agents and their debris, and modulate the inflammatory response. For example, Mres macrophages can protect against tuberculosis by killing Mycobacterium tuberculosis.

Regulatory Macrophages (Mregs)

Mreg macrophages are a type of immunoregulatory macrophages that are induced by IL-10 and TGF-β. Mreg macrophages have a phenotype that is characterized by low expression of MHC II and co-stimulatory molecules, such as CD80 and CD86, and high expression of immunosuppressive molecules, such as PD-L1 and PD-L2.

Mreg macrophages have a function that is mainly inhibition of T cell activation, secretion of immunomodulatory cytokines, such as IL-10 and TGF-β, and promotion of immune tolerance.
Mreg macrophages have a role in disease that is mainly prevention and treatment of autoimmune diseases and transplant rejection. They can suppress the proliferation and differentiation of autoreactive T cells, induce the generation of regulatory T cells, and maintain the balance of immune homeostasis. For example, Mreg macrophages can protect against experimental autoimmune encephalomyelitis by producing IL-10 and TGF-β.

M(Hb) Macrophages

M(Hb) macrophages are a type of hemoglobin-scavenging macrophages that are induced by hemoglobin and CD163. M(Hb) macrophages have a phenotype that is characterized by high expression of CD163 and CD36, and low expression of CD16 and CD32.

M(Hb) macrophages have a function that is mainly clearance of free hemoglobin, degradation of heme and recycling of iron. They can bind and internalize hemoglobin-haptoglobin complexes via CD163, and break down heme into biliverdin and iron via heme oxygenase-1.
M(Hb) macrophages have a role in disease that is mainly protection of vascular endothelial cells, inhibition of oxidative stress and inflammation. They can prevent hemoglobin-mediated cytotoxicity, scavenge free radicals, and produce anti-inflammatory cytokines, such as IL-10 and TGF-β. For example, M(Hb) macrophages can attenuate atherosclerosis by reducing lipid oxidation and foam cell formation.

M(IL-10) Macrophages

M(IL-10) macrophages are a type of anti-inflammatory macrophages that are induced by IL-10 and STAT3. M(IL-10) macrophages have a phenotype that is characterized by low expression of MHC II and co-stimulatory molecules, such as CD80 and CD86, and high expression of IL-10 and TGF-β.

M(IL-10) macrophages have a function that is mainly anti-inflammatory, wound healing and anti-tumoral. They can inhibit the production of pro-inflammatory cytokines, such as TNF-α and IL-6, and enhance the production of anti-inflammatory cytokines, such as IL-10 and TGF-β.
M(IL-10) macrophages have a role in disease that is mainly inhibition of inflammation, promotion of wound healing and suppression of tumor growth. They can modulate the inflammatory response, facilitate tissue repair and regeneration, and induce apoptosis and cytotoxicity of tumor cells. For example, M(IL-10) macrophages can improve the outcome of sepsis by reducing the systemic inflammatory response syndrome.

Tumor-Associated Macrophages (TAMs)

TAMs are tumor-associated macrophages that are derived from the macrophages in the tumor microenvironment. TAMs have a phenotype that is similar to M2, but with some differences, such as higher expression of CD163 and CD206, and lower expression of CD86 and iNOS.

TAMs have a function that is mainly pro-tumoral, angiogenic and invasive. They can promote tumor growth and metastasis by secreting growth factors, such as VEGF and EGF, and matrix metalloproteinases, such as MMP-2 and MMP-9.
TAMs have a role in disease that is mainly facilitation of tumor progression and evasion of immune surveillance. They can enhance tumor angiogenesis, invasion and migration, and suppress anti-tumor immunity by producing immunosuppressive cytokines, such as IL-10 and TGF-β. For example, TAMs can increase the resistance of breast cancer cells to chemotherapy by activating the PI3K/Akt pathway.

Summary of Different Macrophage Subtypes

These different macrophages have distinct features and functions, and play important roles in health and disease. They can modulate inflammation, immunity, tissue repair, iron metabolism, and tumor progression.

Table 1. Summary of different macrophage subtypes

Subtype	Inducer	Phenotype	Function	Role in disease
M3	IL-4 and IL-10	Similar to M2, but higher CD163 and lower CD206	Anti-inflammatory, wound healing and tissue remodeling	Anti-tumoral
Mres	IFN-γ and GM-CSF	Similar to M1, but higher CD64 and lower CD86	Phagocytosis, killing and antiviral	Clearance of infection and inflammation
Mreg	IL-10 and TGF-β	Low MHC II and co-stimulatory molecules, high PD-L1 and PD-L2	Inhibition of T cell activation, secretion of immunomodulatory cytokines, promotion of immune tolerance	Prevention and treatment of autoimmune diseases and transplant rejection
M(Hb)	Hemoglobin and CD163	High CD163 and CD36, low CD16 and CD32	Clearance of free hemoglobin, degradation of heme and recycling of iron	Protection of vascular endothelial cells, inhibition of oxidative stress and inflammation
M(IL-10)	IL-10 and STAT3	Low MHC II and co-stimulatory molecules, high IL-10 and TGF-β	Anti-inflammatory, wound healing and anti-tumoral	Inhibition of inflammation, promotion of wound healing and suppression of tumor growth
TAMs	Tumor microenvironment	Similar to M2, but higher CD163 and CD206, lower CD86 and iNOS	Pro-tumoral, angiogenic and invasive	Facilitation of tumor progression and evasion of immune surveillance

Macrophage research is a rapidly evolving field that faces many challenges and opportunities. Future studies are needed to better understand the molecular mechanisms, functional diversity, and clinical implications of other macrophage types.

Reference

Malyshev, Igor, and Yuri Malyshev. "Current concept and update of the macrophage plasticity concept: intracellular mechanisms of reprogramming and M3 macrophage "switch" phenotype." BioMed Research International 2015 (2015).