The possible mechanisms of chronic pain and depression comorbidity mediated by complement cascade C1q/C3-CR3 and C3/C3a-C3aR
| Complement cascade | Molecular mechanisms | Method/experimental models | Type of disease |
|---|---|---|---|
| C1q | C1q is the hub gene of NP [14] | SNI model, random walk with restart (RWR) methodology [14] | NP |
| C1q | The knockout of C1q led to a significant increase in the mRNA expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the PFC of mice [68] | The LH model of depression [68] | Depression |
| C3 | C3 is the hub gene of NP [13,14] | SNI model, RWR [13,14] | NP |
| C3 | The expression of PFC C3 increased significantly in depressed suicide patients. Chronic stress leads to increased C3 expression in PFC [20] | CUMS mice [20] | Depression |
| C1q/C3 | Neuroinflammation was observed in the glial cells, of the amygdala, C1q and C3 activation, Syn and PSD-95 levels decreased [48] | CRS mice [48] | Chronic pain and depression |
| C1q/C3-CR3 | BoNT/A treatment decreased the levels of complement C3\CR3 and C1q, decreased the colocalization of iba-1 and CD68, decrease the mRNA expression of CX3CR1 in microglia cells, recovered the density of PSD-95, decreased the mRNA levels of TNF-α and IL-1β [49] | PD mouse model, Mice were administered reserpine (3 μg/mL in the drinking water) for 10 wk. BoNT/A (10 U·kg-1·d-1) was injected into the cheek for 3 consecutive days [49] | Chronic pain and depression |
| C1q/C3-CR3 | The mRNA levels of amygdala complement C1q and ITGAM exhibited a significant increase in microglia within the CeA. Iba-1 and PSD95 colocalization levels increased [50] | Fischer-344 rats, micropellets containing either corticosterone (CORT) were bilaterally implanted onto the CeA using stereotaxic techniques [50] | Chronic pain and depression |
| C3/C3a-C3aR | Treatment with hUC-MSCs and a C3aR antagonist resulted in an increase in protein levels of PSD-95 and AMPA, suppressing TNF-β and IL-10. CD16+/Iba1+ in the hippocampus and the level of C3a protein in GFAP+ cells were inhibited by hUC-MSCs [53] | CUMS mice, hUC-MSCs were administered intravenously to CUMS mice once a week for a duration of 4 wk [53] | Chronic pain and depression |
| C3/C3a-C3aR | LPS resulted in the activation of the C3/C3aR in PFC increased polarization of microglia, hUC-MSCs can reduced the C3aR and STAT3, C3aR antagonism treatment restored PSD-95 and SYN levels and improved microglia morphology IL-1R blockers block activation of the pNF-κB/C3 pathway in neurotoxic A1 astrocytes [25] | CUMS mice, hUC-MSCs mice was injected with LPS (0.83 mg/kg, i.p.), The animals received intraperitoneal injections of either saline or C3aR blockade once a day for 4 wk [25] | Chronic pain and depression |
| C3/C3a-C3aR | Gypenoside XVII: resulted in a decrease in the number of Iba1 positive cells and an upregulation of C3 levels, the downregulation of pSTAT3, the levels of IL-1β, IL-6 and TNF-α in the PFC, reduction of VGIut2 within the microglial and PSD95 [54] | CUMS mice, Gypenoside XVII was dissolved in a solution of 0.9% saline containing 0.3% carboxymethyl cellulose and administered orally once daily for a duration of 4 consecutive wk [54] | Chronic pain and depression |
| C3/C3a-C3aR | The downregulation of C3aR was observed to inhibit the activation, of A1 astrocytes induced by LPS, resulting in a decrease in the expression of C3aR, C3, and GFAP. These proteins are known to be involved in the transition from acute to chronic pain [57] | The induction of A1 astrocytes was achieved through intraperitoneal injection of LPS [57] | Chronic pain and depression |
NP: neuropathic pain, SNI: spared nerve injury, TNF-α: tumor necrosis factor-α, IL-1β: interleukin-1β, PFC: prefrontal cortex, LH: learned helplessness, CUMS: chronic unpredictable mild stress, PSD-95: postsynaptic density protein 95, CRS: chronic restraint stress, SYN: synaptophysin, BoNT/A: botulinum neurotoxin A, CX3CR1: C-X3-C motif chemokine receptor 1, PD: Parkinson’s disease, ITGAM: integrin, alpha M, CeA: central nucleus of amygdala, hUC-MSCs: human umbilical cord mesenchymal stem cells, LPS: lipopolysaccharide, STAT3: signal transducer and activator of transcription 3, NF-κB: nuclear factor-kappa B, VGlut2: vesicular glutamate transporter-2.