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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