Creative Biolabs summarizes the current knowledge of the phenotype, function, role in disease, and therapeutic potential of M1 macrophages.

M1 Macrophage Phenotype

M1 macrophages are characterized by a distinct morphology, surface marker expression, cytokine profile, and metabolic status.

• M1 macrophages have a round or oval shape, with a large nucleus and abundant cytoplasm.
• They express high levels of surface markers, such as CD80, CD86, CD40, MHC-II, and TLR4, which enable them to interact with other immune cells and recognize pathogens.
• They also secrete high levels of cytokines, such as TNF-α, IL-1β, IL-6, IL-12, and IL-23, which mediate inflammation and immunity.
• M1 macrophages have a high glycolytic rate and rely on glucose as their main energy source.
• They also produce large amounts of NO and reactive oxygen species (ROS), which are involved in killing pathogens and damaging tissues.

M1 macrophages are not a homogeneous population, but rather consist of different subtypes that have different stimuli and functions. The most well-known subtypes of M1 macrophages are M1a and M1b.

• M1a macrophages are induced by IFN-γ alone or in combination with LPS or other TLR ligands. They produce high levels of NO and IL-12, which are important for anti-microbial and anti-tumor activities.
• M1b macrophages are induced by LPS alone or in combination with other TLR ligands. They produce high levels of TNF-α and IL-6, which are important for inflammation and tissue repair.

The phenotype of M1 macrophages reflects their role in innate immunity and inflammation. However, the phenotype of M1 macrophages is not fixed or stable, but rather dynamic and adaptable to the changing microenvironment. M1 macrophages can switch to M2 macrophages or vice versa under certain conditions or stimuli. This process is called macrophage reprogramming or repolarization.

M1 Macrophage Function

M1 macrophages have various functions that are essential for innate immunity and inflammation. The main functions of M1 macrophages are phagocytosis, antigen presentation, nitric oxide production, and reactive oxygen species generation.

• Macrophage phagocytosis
  • Phagocytosis is the process of engulfing and digesting pathogens, debris, and apoptotic cells by M1 macrophages.
  • Phagocytosis is mediated by different receptors on the surface of M1 macrophages, such as TLRs, scavenger receptors, and Fc receptors.
  • Phagocytosis enables M1 macrophages to clear infections, remove damaged tissues, and prevent autoimmunity.
• Antigen presentation
  • Antigen presentation is the process of displaying fragments of pathogens or self-antigens on the surface of M1 macrophages in association with MHC-II molecules.
  • Antigen presentation is facilitated by the high expression of MHC-II and co-stimulatory molecules, such as CD80, CD86, and CD40, on M1 macrophages.
  • Antigen presentation allows M1 macrophages to activate T cells and initiate the adaptive immune response.
• Nitric oxide production
  • Nitric oxide production is the process of synthesizing NO from L-arginine by the enzyme inducible nitric oxide synthase (iNOS) in M1 macrophages.
  • Nitric oxide production is stimulated by pro-inflammatory cytokines, such as IFN-γ and TNF-α, and TLR ligands, such as LPS.
  • Nitric oxide production endows M1 macrophages with anti-microbial and anti-tumor activities by destroying pathogens and tumor cells.
• Reactive oxygen species generation
  • Reactive oxygen species generation is the process of producing ROS, such as superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH), by the enzyme NADPH oxidase (NOX) in M1 macrophages.
  • Reactive oxygen species generation is induced by pro-inflammatory cytokines, such as IFN-γ and TNF-α, and TLR ligands, such as LPS.
  • Reactive oxygen species generation confers M1 macrophages with anti-microbial and anti-tumor activities by damaging pathogens and tumor cells.
• M1 macrophages also modulate the adaptive immune response by interacting with other immune cells, such as T cells, B cells, and dendritic cells.
  • M1 macrophages can enhance the differentiation and proliferation of Th1 cells by secreting IL-12 and IL-23.
  • M1 macrophages can also inhibit the differentiation and proliferation of Th2 cells by producing NO and ROS.
  • M1 macrophages can also influence the activation and maturation of B cells by expressing CD40 and producing TNF-α.
  • M1 macrophages can also regulate the function and migration of dendritic cells by producing TNF-α and chemokines.

Fig.1 M1 macrophage metabolism.¹

M1 macrophages play a vital role in innate immunity and inflammation by performing various functions. However, these functions can also have detrimental effects on the host when they are excessive or dysregulated.

M1 Macrophages in Disease

M1 macrophages are involved in various diseases, such as infections, autoimmune disorders, atherosclerosis, obesity, diabetes, and neurodegeneration.

• Infections: M1 macrophages are essential for host defense against intracellular pathogens, such as bacteria, viruses, fungi, and parasites. They can kill the pathogens by producing NO or reactive oxygen intermediates (ROI), or by presenting antigens to T cells and activating the adaptive immune response. However, excessive or prolonged activation of M1 macrophages can also cause collateral damage to the host tissues and organs, leading to inflammation and tissue injury.
• Autoimmune Disorders: M1 macrophages play a dual role in autoimmune disorders: they can either initiate or exacerbate the disease by secreting pro-inflammatory cytokines and presenting autoantigens to T cells, or they can limit or resolve the disease by phagocytosing apoptotic cells and producing anti-inflammatory cytokines. The balance between M1 and M2 macrophages is crucial for the regulation of autoimmunity.
• Atherosclerosis: M1 macrophages are involved in the initiation and progression of atherosclerosis by infiltrating the subendothelial space and ingesting oxidized low-density lipoprotein (oxLDL), resulting in the formation of foam cells. Moreover, M1 macrophages can induce apoptosis or necrosis of foam cells and endothelial cells, leading to the release of pro-coagulant factors and thrombosis.

Fig.2 Illustration of the inflammation and remission of acute RA.²

• Neurodegeneration: M1 macrophages are increased in the brain of patients with neurodegenerative diseases. They can exacerbate neuronal damage by producing NO or ROI that induce oxidative stress and neurotoxicity. Additionally, M1 macrophages can phagocytose or degrade amyloid-β (Aβ) plaques in Alzheimer's disease (AD) or α-synuclein aggregates in Parkinson's disease (PD), but they can also release these proteins into the extracellular space or transfer them to other cells via exosomes.

Therefore, M1 macrophages are attractive targets for therapeutic intervention in diseases that are associated with chronic inflammation, tissue damage, and impaired immunity. Several strategies have been proposed to modulate M1 macrophage polarization or function, such as pharmacological agents, natural compounds, gene therapy, or cell therapy. Pharmacological agents can target different aspects of M1 macrophage metabolism, signaling, or cytokine production.

• Inhibitors of glycolysis, such as 2-deoxyglucose (2-DG) or 3-bromopyruvate (3-BP), can suppress M1 macrophage activation and pro-inflammatory cytokine secretion.
• Inhibitors of mTOR, such as rapamycin or metformin, can reduce M1 macrophage polarization and function.
• Inhibitors of NF-κB, such as curcumin or resveratrol, can block M1 macrophage transcriptional program and inflammatory response.
• Inhibitors of NLRP3 inflammasome, such as MCC950 or OLT1177, can prevent M1 macrophage-mediated IL-1β and IL-18 production and pyroptosis.

These pharmacological agents have shown promising results in animal models of inflammatory diseases and cancer. However, these agents also have some limitations and challenges for clinical application. Therefore, more studies are needed to optimize the pharmacological agents that target M1 macrophages in terms of their dosage, delivery, timing, combination, and personalization.

References

1. Geeraerts, Xenia, et al. "Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity." Frontiers in Immunology 8 (2017): 250637.
2. Cutolo, Maurizio, et al. "The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis." Frontiers in Immunology 13 (2022): 867260.