Six Regulators of Macrophage Activity

Macrophages have phagocytic activity and regulate immunity by secreting cytokines, growth factors, etc. They are key coordinators of inflammation, fibrosis, and wound repair, and their activity and polarization are regulated by multiple factors.

Histone Modification

• Histone methylation and demethylation play important roles in macrophage polarization and switching. MLL1, a methyltransferase required for macrophage polarity, increases pro-inflammatory gene expression during the inflammatory phase of wound healing.
• Two other major mechanisms that play a role in macrophage polarity during wound healing include histone acetylation and deacetylation.
• SIRT1, a class of deacetylases, controls the macrophage inflammatory response through deacetylation of IRF-8.
• Sirtuin 3 affects macrophage polarity during wound inflammation.

DNA Methylation

DNA methylation is associated with macrophage plasticity. DNA methylation predominantly inhibits transcription factors that bind to DNA, a process that relies on DNA methyltransferases (DNMT) to deliver methyl to the cytosine ring of DNA.

• DNMT1 controls macrophage phenotypes toward M1. When DNMT1 is inhibited by 5-aza-20 -deoxycytidine, macrophages are induced to assume a more M2 phenotype and inhibit inflammation.
• DNMT3b induces macrophage polarity toward an M1 phenotype, and DNMT3b inhibition also induces macrophage polarity toward an M2 phenotype.

miRNA Regulation

miRNAs alter macrophage polarity by affecting gene expression.

Fig. 1 miRNAs alter macrophage polarity by affecting gene expression.¹

• MiR-146a expression is decreased in M1 macrophages and increased in M2 macrophages. miR-146a inhibits pro-inflammatory cytokines and exerts a protective effect on macrophages.
• MiR-155 expression induces M1 macrophage phenotype and inflammatory responses.
• MiR-21 overexpression is associated with upregulation of pro-inflammatory genes, including IL-1α, TNF-α, iNOS, IL-6, and IL-8, and induces macrophage polarity toward the M1 phenotype.

Metabolic Factors

Macrophage activity in the tumor microenvironment is influenced by a variety of metabolites secreted by tumor cells, fibroblasts, and dying tumor cells, including lactate, glutamine, succinate, α-ketoglutarate, and adenosine.

Immune Cells

Other immune cells have been shown to modulate macrophage phenotype. Th cells secrete different cytokines, among others, to create specific microenvironmental conditions that regulate macrophage polarization and produce different phenotypes.

Fig. 2 Other immune cells modulate macrophage phenotype.²

• Th1 cell-type cytokines such as IFN-γ and TNF-α can lead to the polarization of M0 macrophages into a pro-inflammatory spectrum called M1 macrophages.
• Th2 type cytokines can lead to the polarization of M0 into M2, which can express molecules such as CD206, CD163, and CD209.M2, in response to different cytokines, can be further differentiated into four species with different subtypes.

Other Cells

• Adipocytes. Dermal adipocytes produce palmitate and oleate, as well as MCP-1 and TNF. These adipocyte-produced biomolecules can alter the macrophage inflammatory phenotype and directly affect macrophage function, correlating with macrophage expression of a variety of fatty acid receptors and transporter proteins.
• Keratinocytes. Keratinocytes secrete different cytokines/chemokines that influence the inflammatory profile of immune cells.

For the complex regulatory landscape of macrophages, our scientists offer a comprehensive portfolio of services, including macrophage polarization assays, macrophage polarization phenotype identification and characterization services.

References

1. Locati, Massimo, et al. "Diversity, mechanisms, and significance of macrophage plasticity." Annual Review of Pathology: Mechanisms of Disease 15 (2020): 123-147.
2. Almeida, Fernanda Silva, et al. "Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization." Tropical Medicine and Infectious Disease 8.5 (2023): 276.