Table 1.
Functional plasticity and metabolic regulation in macrophage subsets.
| M1 [LPS(+IFN-γ)] | M2 [IL-4] | |
|---|---|---|
| Stimuli | Classical activation: LPS, IFN-γ, TNF-α, GM-CSF | Alternative activation: IL-4, IL-13, IL-10, TGF-β, IL-33, IL-21 |
| Markers | Surface: CD80/86, MHC-Ⅱ Intracellular: iNOS, IRF5, STAT1, NF-κB, HIF-1α |
Surface: CD163, CD209, CXCR1, CXCR2, Dectin-1 Intracellular: Arginase 1, IRF4, STAT6, PPARγ |
| Function | Pro-inflammatory defense, Phagocytic, Microbial killing, Tissue damage, Anti-cancer immunity, Host defense |
Anti-inflammatory, Wound healing, Efferocytosis, Hypersensitive response, Angiogenesis, Matric and tissue remodeling, Tumor progression and metastasis |
| Secretion | Cytokines: IL-1β, IL-6, IL-12, IL-23, TNF-α Chemokines: CXCL9, CXCL10, CXCL11, MIP-1α (CCL3) Free radicals: ROS, iNOS, NO |
Cytokines: IL-10, IL-1RII, IL-1RA Chemokines: CCL17, CCL18, CCL22, CCL24 Growth factors: TGF-β1, VEGF, PDGF, EGF |
| Glycolysis | Increased glycolytic flux Lactate accumulation HIF-1α-induced production of pro-inflammatory cytokines (IL-1β, etc.) |
Dispensable when OXPHOS is intact Glycolysis produces pyruvate to fuel TCA cycle |
| TCA cycle | Broken in two places: after citrate and after succinate | An intact TCA cycle Replenished with FAO and glutamine metabolism |
| OXPHOS | Dysfunctional OXPHOS and ETC Increased ROS generation |
Increased mitochondrial biogenesis and respiratory capacity PGC1β-induced gene expression |
| PPP | Induced and required for ROS generation via NADPH oxidase, NO production, and nucleotide and protein synthesis | Not required/suppressed by the sedoheptulose kinase CARKL |
| Fatty acid metabolism | Increased lipid synthesis SREBP-induced gene expression |
Increased fatty acid β-oxidation (FAO) STAT6- and PPARγ-induced gene expression |
| Amino acid metabolism | Arginine is converted to NO and citrulline by iNOS Glutamine metabolism regulates trained innate immunity |
Arginase-1 metabolizes arginine to generate ornithine and urea Glutamine is essential for M2 polarization |
| Iron metabolism | Ferritin (iron storage) | Ferroportin (iron export) |
Abbreviations: M1, classically activated macrophages; M2, alternatively activated macrophages; LPS, lipopolysaccharide; TNF-α, Tumor necrosis factor-α; GM-CSF, granulocyte-macrophage colony-stimulating factor; TGF-β, transforming growth factor-β; MHC, major histocompatibility complex class; iNOS, inducible nitric oxide synthase; IRF, interferon regulatory factor; STAT, signal transducer and activator of transcription; NF-κB, nuclear factor-κB; PPAR, peroxisome proliferator activated receptor; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor; EGF, epidermal growth factor; FAO, fatty acid β-oxidation; PGC-1β, PPARγ coactivator 1β; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation; ETC, electron transport chain; PPP, pentose phosphate pathway.