Inflammatory monocyte-derived macrophages drive pain via their production of nerve growth factor after peripheral nerve injury in mice

Immune cells are vital to regeneration and repair processes in the nervous system. We previously reported that myeloid cells play a critical role in nerve regeneration and locomotor recovery after peripheral nerve injury (PNI) by facilitating the clearance of inhibitory myelin debris, promoting angiogenesis, and producing neurotrophins (NTs) such as nerve growth factor (NGF), brain-derived neurotrophic factor, NT-3 and NT-4/5. Here, we show that NTs are synthesized by various types of myeloid cells after PNI, including neutrophils, macrophages and dendritic cells. Notably, we found that within the first week of PNI in male and female mice, monocyte-derived Cd11b + Cd68 + Ly6B + Ly6C hi macrophages infiltrate the sciatic nerve in an interleukin (IL)-1-dependent but CCR2-independent manner, and then locally produce mature NGF. Accordingly, depletion of circulating monocytes using PLX73086, a CSF1R inhibitor unable to cross blood-nervous system barriers, reduced NGF mRNA levels in the sciatic nerve distal stump. When polarized toward a proinflammatory phenotype in vitro , mouse macrophages rapidly release the cleaved form of NGF. Further analysis revealed that systemic administration of an anti-NGF neutralizing antibody reduced mechanical pain in mice with PNI. Together with our previous work, these results suggest that infiltrating monocyte-derived macrophages release NGF, thereby promoting both peripheral nerve regeneration and pain following injury. Significance statement We unveil a pivotal role for nerve growth factor (NGF) in the modulation of pain following peripheral nerve injury (PNI). Our comprehensive investigation traces augmented NGF mRNA and protein levels during the initial week post-PNI, pinpointing the involvement of macrophages with a distinct immunophenotypic signature in NGF production. Strategic depletion experiments demonstrate monocyte-derived macrophage production of NGF in the nerve distal stump. Cultured macrophages, when polarized toward a proinflammatory phenotype, release mature NGF. Moreover, systemic NGF neutralization alleviates pain sensitivity post-PNI. This research identifies key molecular intricacies governing NGF expression and release by inflammatory macrophages, offering promising targets for therapeutics in pain management and peripheral nerve regeneration after injury.