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

Abstract

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 proinflammatory and anti-inflammatory cytokine expression patterns. We further applied coculture 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 patients with SFN than in controls. NTN1 slows and reduces murine sensory neurite outgrowth in vitro, but does not alter keratinocyte cytokine expression. In the naive state, keratinocytes of patients with SFN 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 with baseline (P < 0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared with healthy controls and further supports the concept of cutaneous nociception.

Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels

“…A recent study shows that keratinocytes are involved in nerve fiber degeneration in small nerve neuropathy patients. In patients suffering from small fiber neuropathy, axon guidance cue netrin-1 is highly expressed in patients’ keratinocytes which can reduce sensory neurite outgrowth ( Kress et al, 2021 ). Hence, the hypoinnervation could be an indirect effect of TRPV3 hyperactivity in non-neuronal skin cells such as keratinocytes that closely monitor or affect the epidermal sensory terminals.…”

Molecular and cellular mechanisms of itch and pain in atopic dermatitis and implications for novel therapeutics

“… 99 , 100 Additional pain mediators include bradykinin, ATP, P2X purinoceptor 3 agonists, proteases, TLR agonists, cytokines (IL‐1, IL‐6, IL‐8, IL‐17, IL‐33, TSLP and TNF‐α), neurotrophins including NGF, ET‐1, CGRP, MrgprX1, MrgprX2 and MrgprD and ion channels (TRPVs, TRPA1, acid‐sensing ion channels, potassium ions and sodium ions). 60 , 77 , 101 , 102 , 103 , 104 , 105 , 106 The activity of many of these molecules is mediated by various populations of primary afferent fibres (e.g. peptidergic and nonpeptidergic) that synapse in different layers of the dorsal horn of the spinal cord.…”

Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature

“…Considering the intimate relationship between fibroblasts and the immune system, it is therefore unsurprising that, already two decades ago, they were included on a list of cells thought to be capable of inducing peripheral neuron sensitisation 20. Since then, however, they seem to have engendered little interest, with the exception, perhaps, of synovial fibroblasts in the knee21 and recent pioneering work on fibroblasts taken from patients with small fibre neuropathy and fibromyalgia 22–24. However, fibroblasts are a key component of our body’s inflammatory response,25–27 and abnormal fibroblast function has been implicated in painful immune-mediated diseases like arthritis 28–30.…”

“…20 Since then, however, they seem to have engendered little interest, with the exception, perhaps, of synovial fibroblasts in the knee 21 and recent pioneering work on fibroblasts taken from patients with small fibre neuropathy and fibromyalgia. [22][23][24] However, fibroblasts are a key component of our body's inflammatory response, [25][26][27] and abnormal fibroblast function has been implicated in painful immune-mediated diseases like arthritis. [28][29][30] They therefore seem a sensible cell type to explore in the study of peripheral sensitisation.…”