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. 2023 Oct 10;14:1193053. doi: 10.3389/fimmu.2023.1193053

Figure 2.

Figure 2

Microglial activation and their roles in depression. Ramified microglia stimulated by PAMPs or DAMPs are activated into three main microglial morphotypes, including hyper-ramified, activated, and amoeboid types. Alternatively, two main polarization states are defined in activated microglia: M1 and M2 phenotypes. The classic M1 polarization microglia is usually marked with iNOS, CD86, CD16 and MHC‐II. Under the M1 state, exposure to LPS and/or IFN‐γ stimulates and binds to TLR-4 or IFN‐γ receptors, respectively, leading to the activation of NF‐κB and STAT1. Meanwhile, the increase in iNOS produces a burst of ROS and RNS. All these lead to the excessive release of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-12, and chemokines, such as CXCL9, CXCL10, CCL2, and ROS, which produce neurotoxic effects on the neurons in CNS. The alternative M2 polarization microglia is usually marked with ARG-1, CD206 and CD163. M2 microglia can also be divided into three subtypes including M2a, M2b and M2c, because of the different stimulis. Upon stimulation with IL‐4/IL‐13, the cells transform into the M2a-phenotype microglia with an increase in IL-10, CCL17 and CCL18. Exposed to TLR ligands and immune complexes, the cells transform into the M2b-phenotype microglia with an expression of IL-6. Upon stimulation with IL-10, the cells transform into the M2c-phenotype microglia with an increase in IL-4, TGF-β and CCL16. The phenotypes of M1 microglia perform functions that aberrant phagocytosis of synapses leading to produce neurotoxic effects on the neurons in CNS. The phenotypes of M2 microglia perform functions that neurotrophic support leading to produce neuroprotective effects on the neurons in CNS. Thus, the imbalance of M1 and M2 polarization induces increased excessive neurotoxicity and decreased neuroprotection, leading to depression. PAMPs pathogen-associated molecular patterns, DAMPs danger-associated molecular patterns, iNOS inducible nitric oxide synthase, CD86 cluster of differentiation 86, CD16 cluster of differentiation 16, MHC‐II major histocompatibility complex II, LPS lipopolysaccharide, IFN‐γ interferon gamma, TLR-4 toll-like receptor 4, NF‐κB transcription factors nuclear factor kappa-B, STAT1 signal transducer and activator of transcription 1, ROS reactive oxygen species, RNS reactive nitrogen species, TNF-α tumor necrosis factor α, IL-1β Interleukin-1β, Interleukin-6 IL-6, Interleukin-12 IL-12, CXCL9 chemokine (C-X-C motif) ligand 9, CXCL10 chemokine (C-X-C motif) ligand 10, CCL2 chemokines chemoattractant cytokine ligand 2, CNS central nervous system, ARG-1 arginase-1, CD206 cluster of differentiation 206, CD163 cluster of differentiation 163, IL‐4 interleukin-4, IL‐13 interleukin-13, IL-10 interleukin-10, CCL17 chemoattractant cytokine ligand 17, CCL18 chemoattractant cytokine ligand 18, IL-1 interleukin-1, Interleukin-10, IL-10 Interleukin-4 IL-4, TGF-β transforming growth factor-β, CCL16 chemoattractant cytokine ligand 16.