Differential impact of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in small fiber neuropathy.

Peripheral denervation and pain are hallmarks of small fiber neuropathy (SFN). We investigated the contribution of skin cells on nociceptor degeneration and sensitization. We recruited 56 patients with SFN and 31 healthy controls, and collected skin punch biopsies for immunohistochemical and immunocytochemical analysis of netrin-1 (NTN1) and pro- and anti-inflammatory cytokine expression patterns. We further applied co-culture systems with murine dorsal root ganglion (DRG) neurons for skin cell-nerve interaction studies and patch-clamp analysis. Human keratinocytes attract murine DRG neuron neurites and the gene expression of the axon guidance cue NTN1 is higher in keratinocytes of SFN patients than in controls. NTN1 slows and reduces murine sensory neurite outgrowth in vitro, but does not alter keratinocyte cytokine expression. In the naïve state, keratinocytes of SFN patients show a higher expression of transforming growth factor-β1 (p<0.05), while fibroblasts display higher expression of the algesic cytokines interleukin (IL)-6 (p<0.01) and IL-8 (p<0.05). IL-6 incubation of murine DRG neurons leads to an increase in action potential firing rates compared to baseline (p<0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared to healthy controls and further supports the concept of cutaneous nociception.