Korean J Pain.  2024 Apr;37(2):91-106. 10.3344/kjp.23284.

The complement system: a potential target for the comorbidity of chronic pain and depression

• Tang S
• Hu W
• Zou H
• Luo Q
• Deng W
• Cao S

• KMID: 2554950
• DOI: http://doi.org/10.3344/kjp.23284

Abstract

The mechanisms of the chronic pain and depression comorbidity have gained significant attention in recent years. The complement system, widely involved in central nervous system diseases and mediating non-specific immune mechanisms in the body, remains incompletely understood in its involvement in the comorbidity mechanisms of chronic pain and depression. This review aims to consolidate the findings from recent studies on the complement system in chronic pain and depression, proposing that it may serve as a promising shared therapeutic target for both conditions. Complement proteins C1q, C3, C5, as well as their cleavage products C3a and C5a, along with the associated receptors C3aR, CR3, and C5aR, are believed to have significant implications in the comorbid mechanism. The primary potential mechanisms encompass the involvement of the complement cascade C1q/C3-CR3 in the activation of microglia and synaptic pruning in the amygdala and hippocampus, the role of complement cascade C3/C3a-C3aR in the interaction between astrocytes and microglia, leading to synaptic pruning, and the C3a-C3aR axis and C5a-C5aR axis to trigger inflammation within the central nervous system. We focus on studies on the role of the complement system in the comorbid mechanisms of chronic pain and depression.

Keyword

Astrocytes; Central Nervous System; Chronic Pain; Complement System Proteins; Comorbidity; Depression; Inflammation; Microglia; Neuronal Plasticity

Figure

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  Fig. 1 Activation pathways of the complement system. The complement system is activated by the classical, lectin, or alternative pathways. The initiation of the classical pathway involves the C1 protein complex, which consists of C1q, C1r, and C1s. Upon activation, C1s cleaves C4 and C2. In the lectin pathway, activation occurs when mannose-binding lectin (MBL) encounters a pathogenic carbohydrate motif. Subsequently, MBL associates with MASP-1 and MASP-2, leading to the cleavage of C4 and C2. The resulting cleavage products induce the formation of C3 convertase C4bC2a, which subsequently splits C3 into C3a and C3b. C3a has the ability to induce the chemotaxis and activation of microglia via C3aR. Additionally, C3b can undergo cleavage to form iC3b, which is recognized by microglial cells through complement receptor 3 (CR3), thereby promoting activation. Furthermore, the production of C3b can facilitate the generation of C5 convertase (C4bC2aC3b, C3bBbC3b). C5 can also be cleaved into C5a and C5b, with C5a further promoting the chemotaxis and activation of glial cells through C5aR. Another pathway involves the spontaneous hydrolysis of C3 to C3 (H2O). All three pathways result in the generation of convertases, which subsequently stimulate the production of the primary components of the complement system, namely anaphylatoxins (C4a, C3a, and C5a), membrane attack complexes, and opsonins (C3b). Allergic toxins initiate pro-inflammatory signaling, while C5b associates with C6, C7, C8, and C9 to form membrane attack complexes (MAC), ultimately resulting in cell cleavage.

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  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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  Fig. 3 Potential mechanisms in which neuroinflammation is mediated by the complement system is involved in the comorbidity of chronic pain and depression. Complement cascade C3a-C3aR pathway. Under the influence of injury and inflammation, astrocytes have the ability to enhance the production of complement C3a. This molecule then interacts with the receptor C3aR found on microglia, resulting in the promotion of M1 type polarization of microglia in specific regions of the central nervous system, including the dorsal horn of the spinal cord, dorsal root neurons in the spinal cord, hippocampus, and prefrontal cortex. Consequently, this process leads to an upregulation of the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and NLRP3 in the hippocampus, as well as an elevation in the levels of the inflammatory cytokine IL-1β in the prefrontal cortex. These events ultimately induce neuroinflammation, which is closely associated with the development of chronic pain and depression. Complement cascade C5a-C5aR pathway. Response to injury and inflammation, astrocytes have the capacity to elevate the expression of complement C5a. The interaction between C5a and its receptor (C5aR) can subsequently enhance the secretion of pro-inflammatory factors via the activation of p38MAPK and ERK1/2 signaling pathways. This process further facilitates the M1-type polarization of microglia in the spinal dorsal horn and dorsal root ganglion (DRG), thereby inducing neuroinflammation. Ultimately, these events contribute to the development of chronic pain and depression. TNF-α: tumor necrosis factor-α, IL-1β: interleukin-1, NLRP3: NOD-like receptor protein 3.

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