What are the key differences between M1 (classically activated) and M2 (alternatively activated) macrophages?

M1 vs M2 Macrophages: Key Functional and Metabolic Differences

M1 macrophages are classically activated, pro-inflammatory cells that rely on glycolysis and produce reactive oxygen species (ROS) and pro-inflammatory cytokines to eliminate pathogens, while M2 macrophages are alternatively activated, anti-inflammatory cells that depend on oxidative phosphorylation and promote tissue repair, phagocytosis of debris, and resolution of inflammation. 1

M1 Macrophages (Classically Activated)

Activation Triggers

• Induced by LPS, TNF-α, and IFN-γ exposure, which drives their differentiation from infiltrating monocytes recruited by MCP-1 and GM-CSF 1
• Innate lymphoid cells contribute to M1 differentiation during the acute inflammatory phase 1

Metabolic Profile

• Predominantly utilize aerobic glycolysis rather than oxidative phosphorylation, representing a fundamental metabolic switch upon activation 1, 2
• Display two breaks in the TCA cycle that result in accumulation of itaconate (a microbicidal compound) and succinate 2
• Excess succinate stabilizes HIF-1α, which activates transcription of glycolytic genes and sustains the glycolytic phenotype 2

Functional Characteristics

• Produce high levels of ROS, nitric oxide (NO), and hydrolytic enzymes required for effectively eradicating invading pathogens 1
• Secrete pro-inflammatory cytokines including TNF-α, IL-1α, IL-1β, IL-6, IL-8, and IL-12 1, 3, 2
• Induce polarization of T cells into the Th1 phenotype, establishing long-term inflammatory responses that include adaptive immunity 1, 3
• Central role in host defense against infection and initiating inflammatory responses 4

Clinical Context

• In acute pulmonary embolism, M1 macrophages infiltrate the RV outflow tract within 18 hours 1
• Protumorigenic in certain contexts, as M1 polarization can be regulated by T lymphocytes in the tumor microenvironment 1

M2 Macrophages (Alternatively Activated)

Activation Triggers

• Induced by anti-inflammatory mediators TGF-β and IL-10, along with IL-4 and IL-13 1, 3, 5
• Predominate 6 weeks after acute right ventricular pressure overload, contributing to repair processes 1

Metabolic Profile

• Primarily dependent on oxidative phosphorylation (OXPHOS) with an intact TCA cycle 1, 2
• The TCA cycle provides substrates for the electron transport chain complexes, supporting their energy requirements 2
• Characterized by specific pathways regulating lipid and amino acid metabolism that support their anti-inflammatory functions 2

Functional Characteristics

• Display upregulated phagocytic capacity aimed at clearing tissue from cellular debris left from prior neutrophilic attack 1
• Produce anti-inflammatory cytokines, particularly IL-10, which regulates negative feedback on pro-inflammatory macrophage activity 3, 5
• Contribute to tissue maturation through reorganization of extracellular matrix and vasculature during the remodeling phase, a process that can take up to years 1
• Promote resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, and coordinate tissue integrity 2
• Release anti-inflammatory mediators and neurotrophic factors including growth factors that support tissue repair 2

Clinical Context

• In chronic right ventricular pressure overload, secretory M2 macrophages predominate and contribute to repair 1
• In metabolic dysfunction-associated steatotic liver disease, M2 macrophages contribute to increased GDF15 levels as a stress-induced compensatory mechanism 1

Critical Distinctions for Clinical Practice

Temporal Dynamics

• M1 macrophages dominate early inflammatory phases (within hours to days), while M2 macrophages emerge during resolution phases (weeks to months) 1, 5
• The switch from M1 to M2 is promoted by downregulation of inflammatory mediators and upregulation of TGF-β and IL-10 1, 5

Metabolic Switching as a Therapeutic Target

• The metabolic phenotype directly supports functional polarization: glycolysis enables rapid inflammatory responses in M1, while OXPHOS supports sustained phagocytic and repair functions in M2 2
• Modulating macrophage polarization by targeting metabolic pathways holds promise for treating inflammatory diseases 6, 4

Common Pitfalls

• M1 and M2 represent extremes of a continuum, not discrete populations; macrophages exist along a spectrum of activation states in vivo 7, 4
• Context matters: in tumors, M2 macrophages can be protumorigenic, while M1 can be antitumor, though T lymphocyte interactions regulate this balance 1
• Persistent M1 inflammation without transition to M2 leads to chronic tissue damage, while premature M2 activation may allow pathogen persistence 1, 5

Starvation Effects

• Acute starvation increases M1 macrophage effector function in certain infections (e.g., Listeria monocytogenes), decreasing bacterial load and mortality 1
• M1 and dendritic cells switch to glycolysis upon activation, while M2 macrophages and T regulatory cells rely on fatty acid oxidation and OXPHOS, making M2 potentially more resilient during nutrient restriction 1