Figure 2.

Interactions between the distal part of nociceptors with different immune cells. When injury and infection happen, macrophages are induced to produce DAMP and PAMP. They activate TLRs expressed in nociceptive neurons and up-regulate the expression of MyD88, which promotes the MAPK signaling pathway through NF-κB. MyD88 also activates sodium channels in sensory neurons, increasing the excitability of the nociceptors. T cells release IL-4 to activate B cells, which produce CRPSI IgM and IgG. CRPS IgM, binding to the corresponding neoantigens. The antigen-IgM complex promotes complements (e.g., C5a), leading to increased expression of pro-inflammatory cytokines and peripheral sensitization.