FIGURE 1.

Monocyte infiltration into DRG and peripheral nervous tissue in vincristine-induced neuropathic pain. (1) Under steady-state conditions Ly6C^-CX₃${\mathrm{CR}}_{\mathrm{1}}^{\mathrm{+}}$${\mathrm{CCR}}_{\mathrm{2}}^{\mathrm{–}}$ monocytes, which patrol the endothelium, dominate over inflammatory Ly6C⁺CX₃${\mathrm{CR}}_{\mathrm{1}}^{\mathrm{–}}$${\mathrm{CCR}}_{\mathrm{2}}^{\mathrm{+}}$ monocytes in the circulation. (2) During adverse conditions such as those that occur following chemotherapy exposure, CX₃${\mathrm{CR}}_{\mathrm{1}}^{\mathrm{+}}$ monocytes infiltrate through the endothelium and into nervous tissue in a soluble CX₃CL₁-dependent manner, which is produced by cleavage mediated by ADAM17 in adverse conditions (3). (4) CX₃${\mathrm{CR}}_{\mathrm{1}}^{\mathrm{+}}$ monocytes differentiate into macrophages in nervous tissue where they express reactive oxygen species (ROS). ROS activation of TRPA1 channels in peripheral nerve fibers evokes pain. (5) During adverse conditions, Ly6C⁺${\mathrm{CCR}}_{\mathrm{2}}^{\mathrm{+}}$ monocytes also infiltrate into peripheral nervous tissue in a CCL₂-dependent manner. (6) ${\mathrm{CCR}}_{\mathrm{2}}^{\mathrm{+}}$ macrophages in tissue generate cytokines, which activate nociceptive fibers. (7) Indirect evidence suggests the presence of CCL₂ in the periphery can serve as a positive feedback mechanism by which infiltration of ${\mathrm{CCR}}_{\mathrm{2}}^{\mathrm{+}}$ monocytes is increased further.