Investigation of the growth-modulating and axon-sensitizing effect of keratinocytes and fibroblasts on intraepidermal nerve fibers

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Small fiber neuropathies (SFN) are a subgroup of sensory neuropathies, which is characterized by functional impairment of small caliber A-delta and C-nerve fibers with localized burning pain at toes and feet. The typical histological finding is a reduction or a complete loss of the intraepidermal nerve fibers (IENF). It is assumed that keratinocytes and fibroblasts play an active role in the induction and maintenance of focal neuropathic pain in SFN. It is unclear why IENF degenerate, how reduction and loss of nociceptors leads to increased pain, and why IENF density does not correlate with the extent of pain. The hypothesis followed in this project is that keratinocytes and fibroblasts modulate axonal growth by the secretion of axon guidance proteins like netrins and that these cutaneous netrins induce the production of algesic pro-inflammatory cytokines by kerationocytes and fibroblasts. These cytokines may then activate the remaining IENF and induce pain. This hypothesis will be tested with a clinical and experimental approach using keratinocyte and fibroblast cultures obtained from skin punch biopsies of patients with SFN compared to healthy controls. The interaction of keratinocytes and fibroblasts with neuritis will be analyzed in oligo-compartimented co-culture systems. The findings will improve the understanding of pain pathophysiology and will provide potential targets for new therapy strategies.