Skin pain is a common but poorly understood symptom of psoriasis, affecting only a subset of patients. Using imiquimod and interleukin-17A-induced psoriasiform mouse models that exhibited pain-like behaviors, we found that nerve growth factor (NGF) levels were elevated in lesional skin, activating TrkA signaling in dorsal root ganglion neurons and promoting Schwann-cell hypertrophy. Normally, Schwann cells (SCs) limit NGF signaling in cutaneous peripheral nerves through the p75NTR receptor. However, inflammation driven by interleukin-17A increased non-muscle myosin II activity and elevated NGF levels, leading to the internalization and degradation of p75NTR. The resulting depletion of p75NTR caused local NGF accumulation, excessive TrkA activation, and heightened pain sensitivity. These findings reveal that psoriatic inflammation converts SCs from protective buffers into drivers of pain, offering a mechanistic explanation for why only some patients experience cutaneous pain in psoriasis.
wang et al. (Fri,) studied this question.