Figure 1. The interaction between macrophages and sensory nerves.
  1. Sensory nerves release SP and CGRP promote either M1 phenotype or M2 phenotype.
  2. M1 macrophages produce pro-inflammatory cytokines including CCL2, IL-1β, TNF-α, IL-6, PGE2, NGF, IGF-1 which combine to the specific receptors on sensory nerves and enhance the activity of cation channels like TRPV1/TRAV1 and NaV1.7/1.8/1.9 via cell signals (cAMP, PKA, PKC, PI3K, MAPKs, NF-κB, JAK, STAT, and Src).
  3. Sensory nerves secret CCL2 and CX3CL1 which stimulate CCR2 and CX3CR1 on macrophages and microglia.
  4. M2 macrophages express IL-10, TGF-β, GPR37, opioid peptides. IL-10 can downregulate TTX-S and Nav1.8 sodium channels. TGF-β inhibit pro-inflammatory cytokine production through p38 MAPK. Opioid peptides bind to opioid receptors µ (mu), δ (delta) and κ (kappa). Activation of GPR37 induces phagocytosis.