Fig. 2. Potential mechanisms by glial cell synaptic pruning mediated by the complement system in chronic pain and depression comorbidity. Complement cascade C1q/C3-CR3 pathway. The amygdala and hippocampus exhibit heightened activation of complement C1q and C3 in response to stimuli associated with chronic pain and depression. This activation facilitates the differentiation of microglial cells into a pro-inflammatory M1 phenotype. Complement C3 undergoes lysis, leading to the generation of C3b and iC3b. This iC3b acts as a marker for synapses, facilitating their identification by the CR3 receptor on pro-inflammatory M1 microglial cells, potentially resulting in synaptic pruning. Notably, there is a reduction in the levels of synaptic proteins SYP and PSD95, as well as a decrease in the secretion of the VGlut2. The BonT/A can counteract these changes by inhibiting the activation of C1q and C3, thereby reducing synaptic pruning in microglia. Complement cascade C3/C3a-C3aR signals pathway. In the presence of LPS or chronic stress, neurotoxic A1 astrocytes in the prefrontal cortex become activated, resulting in an increase in complement C3 and C3a levels. Specifically, C3a targets the C3aR receptor on microglial cells, promoting their polarization towards an M1 phenotype. This activation further stimulates the STAT3 and NF-κB pathways in microglial cells. This amplifies synaptic pruning in microglia and hUC-MSCs, IL-1R, and Gynostemma inhibit and improve these processes. PSD95: postsynaptic density protein 95, VGlut2: vesicular glutamate transporter-2, BoNT/A: botulinum neurotoxin A, LPS: lipopolysaccharide, STAT3: signal transducer and activator of transcription 3, NF-κB: nuclear factor-kappa B, hUC-MSCs: human umbilical cord mesenchymal stem cells.
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