Fibromyalgia vs small fiber neuropathy: diverse keratinocyte transcriptome signature

Abstract

Damage to thinly myelinated and unmyelinated nerve fibers causes small fiber pathology, which is increasingly found in pain syndromes such as small fiber neuropathy (SFN) and fibromyalgia syndrome (FMS). The peripheral nerve endings of the small nerve fibers terminate within the epidermis, where they are surrounded by keratinocytes that may act as primary nociceptive transducers. We performed RNA sequencing of keratinocytes obtained from patients with SFN, FMS, and healthy controls. We found 141 deregulated protein coding genes between SFN patients and healthy controls and no differentially expressed genes between patients with FMS and healthy controls. When comparing patients with SFN with patients with FMS, we detected 167 differentially expressed protein coding genes (129 upregulated and 38 downregulated). Further analysis revealed enriched inflammatory pathways. Validation of selected candidates in an independent cohort confirmed higher expression of the proinflammatory mediators interleukin-8, C-X-C motif chemokine 3, endothelin receptor type A, and the voltage-gated sodium channel 1.7 in SFN compared with patients with FMS. We provide a diverse keratinocyte transcriptome signature between patients with SFN and patients with FMS, which may hint toward distinct pathomechanisms of small fiber sensitization in both entities and lay the basis for advanced diagnostics.

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

“…Further, recent studies have highlighted anti-tumour therapeutic potential; a novel synthetic AMP, Ranatuerin-2PLx, inhibited prostate cancer cell proliferation in vitro (37). The role of keratinocytes in patients with small fiber pathology has recently been studied using transcriptomic analysis of skin biopsies, revealing an enrichment of inflammatory pathways with higher expression of algesic mediators in keratinocytes (38).…”

Keratinocyte Piezo1 drives paclitaxel-induced mechanical hypersensitivity

“…Our findings provide rational for the development of therapeutics targeted at keratinocytes and epidermal Piezo1 for alleviating paclitaxel-induced pain. Furthermore, alterations in keratinocyte function and signaling have been described in a variety of painful inflammatory and neuropathic conditions that affect the skin; these include the devastating painful conditions complex regional pain syndrome, post-herpetic neuralgia, and fibromyalgia 62,63 . The potential contribution of keratinocyte mechanotransduction to mechanical pain in these conditions should be explored.…”

Small fiber neuropathies: expanding their etiologies

“…If similar diagnostic tests indeed show small nerve fiber pathology in both fibromyalgia and SFN, there is need for better discriminatory tests. The keratinocyte transcriptome signature might be helpful in this [40 ▪▪ ]. In 26 SFN and 26 fibromyalgia patients, the RNA sequencing of keratinocytes showed a diverse transcriptome signature with differentially expressed protein coding genes.…”