Fibromyalgia vs small fiber neuropathy: diverse keratinocyte transcriptome signature.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 10 2021
01 10 2021
Historique:
received:
20
11
2020
accepted:
15
02
2021
pubmed:
7
3
2021
medline:
25
2
2023
entrez:
6
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33675632
doi: 10.1097/j.pain.0000000000002249
pii: 00006396-202110000-00013
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2569-2577Informations de copyright
Copyright © 2021 International Association for the Study of Pain.
Références
Bäckryd E, Tanum L, Lind AL, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res 2017;10:515–25.
Baumbauer KM, DeBerry JJ, Adelman PC, Miller RH, Hachisuka J, Lee KH, Ross SE, Koerber HR, Davis BM, Albers KM. Keratinocytes can modulate and directly initiate nociceptive responses. Elife 2015;4:e09674.
Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008;131(pt 7):1912–25.
Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci 2013;14:49–62.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.
Dolcino M, Tinazzi E, Puccetti A, Lunardi C. Gene expression profiling in fibromyalgia indicates an autoimmune origin of the disease and opens new avenues for targeted therapy. J Clin Med 2020;9:1814.
Eich W, Hauser W, Arnold B, Jackel W, Offenbacher M, Petzke F, Schiltenwolf M, Settan M, Sommer C, Tolle T, Uceyler N, Henningsen P; Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. Fibromyalgia syndrome. Definition, classification, clinical diagnosis and prognosis [in German]. Schmerz 2012;26:247–58.
Evdokimov D, Frank J, Klitsch A, Unterecker S, Warrings B, Serra J, Papagianni A, Saffer N, Meyer Zu Altenschildesche C, Kampik D, Malik RA, Sommer C, Üçeyler N. Reduction of skin innervation is associated with a severe fibromyalgia phenotype. Ann Neurol 2019;86:504–16.
Evdokimov D, Kreß L, Dinkel P, Frank J, Sommer C, Üçeyler N. Pain-associated mediators and axon pathfinders in fibromyalgia skin cells. J Rheumatol 2020;47:140–8.
Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012;71:26–39.
Iwasa T, Afroz S, Inoue M, Arakaki R, Oshima M, Raju R, Waskitho A, Inoue M, Baba O, Matsuka Y. IL-10 and CXCL2 in trigeminal ganglia in neuropathic pain. Neurosci Lett 2019;703:132–8.
Jones KD, Gelbart T, Whisenant TC, Waalen J, Mondala TS, Ikle DN, Salomon DR, Bennett RM, Kurian SM. Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia. Clin Exp Rheumatol 2016;34(2 suppl 96):S89–98.
Karl F, Wussmann M, Kreß L, Malzacher T, Fey P, Groeber-Becker F, Üçeyler N. Patient-derived in vitro skin models for investigation of small fiber pathology. Ann Clin Transl Neurol 2019;6:1797–806.
Khodorova A, Montmayeur JP, Strichartz G. Endothelin receptors and pain. J Pain 2009;10:4–28.
Kreß L, Hofmann L, Klein T, Klug K, Saffer N, Spitzel M, Bär F, Sommer C, Karl F, Üçeyler N. Differential impact of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in small fiber neuropathy. PAIN 2021;162:1262–72.
Kumamoto J, Nakatani M, Tsutsumi M, Goto M, Denda S, Takei K, Denda M. Coculture system of keratinocytes and dorsal-root-ganglion-derived cells for screening neurotrophic factors involved in guidance of neuronal axon growth in the skin. Exp Dermatol 2014;23:58–60.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014;30:923–30.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550.
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 2011;17:10–12
McDermott LA, Weir GA, Themistocleous AC, Segerdahl AR, Blesneac I, Baskozos G, Clark AJ, Millar V, Peck LJ, Ebner D, Tracey I, Serra J, Bennett DL. Defining the functional role of NaV1.7 in human nociception. Neuron 2019;101:905–19 e908.
Moehring F, Cowie AM, Menzel AD, Weyer AD, Grzybowski M, Arzua T, Geurts AM, Palygin O, Stucky CL. Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. Elife 2018;7:e31684.
Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. PAIN 2013;154:2310–16.
Piotrowska A, Rojewska E, Pawlik K, Kreiner G, Ciechanowska A, Makuch W, Nalepa I, Mika J. Pharmacological blockade of spinal CXCL3/CXCR2 signaling by NVP CXCR2 20, a selective CXCR2 antagonist, reduces neuropathic pain following peripheral nerve injury. Front Immunol 2019;10:2198.
Radtke C, Rennekampff HO, Reimers K, Vogt PM, Kocsis JD. Paracrine loop of keratinocyte proliferation and directed neuritic outgrowth in a neuroepithelial coculture. Ann Plast Surg 2013;70:162–7.
Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S, Sprott H. Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol 2003;30:146–50.
Sanchez-Dominguez B, Bullon P, Roman-Malo L, Marin-Aguilar F, Alcocer-Gomez E, Carrion AM, Sanchez-Alcazar JA, Cordero MD. Oxidative stress, mitochondrial dysfunction and, inflammation common events in skin of patients with Fibromyalgia. Mitochondrion 2015;21:69–75.
Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 2014;75:196–208.
Talagas M, Lebonvallet N, Berthod F, Misery L. Lifting the veil on the keratinocyte contribution to cutaneous nociception. Protein Cell 2020;11:239–50.
Talagas M, Lebonvallet N, Leschiera R, Sinquin G, Elies P, Haftek M, Pennec JP, Ressnikoff D, La Padula V, Le Garrec R, L'Herondelle K, Mignen O, Le Pottier L, Kerfant N, Reux A, Marcorelles P, Misery L. Keratinocytes communicate with sensory neurons via synaptic-like contacts. Ann Neurol 2020;88:1205–19.
Üçeyler N. Small fiber pathology—a culprit for many painful disorders? PAIN 2016;157(suppl 1):S60–66.
Uçeyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, Sommer C. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology 2010;74:1806–13.
Üçeyler N, Kewenig S, Kafke W, Kittel-Schneider S, Sommer C. Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls. BMC Neurol 2014;14:185.
Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013;136(pt 6):1857–67.
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62:600–10.
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 1990;33:160–72.
Wu LY, Li M, Qu ML, Li X, Pi LH, Chen Z, Zhou SL, Yi XQ, Shi XJ, Wu J, Wang S. High glucose up-regulates Semaphorin 3A expression via the mTOR signaling pathway in keratinocytes: a potential mechanism and therapeutic target for diabetic small fiber neuropathy. Mol Cell Endocrinol 2018;472:107–16.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012;16:284–7.
Zhao P, Barr TP, Hou Q, Dib-Hajj SD, Black JA, Albrecht PJ, Petersen K, Eisenberg E, Wymer JP, Rice FL, Waxman SG. Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. PAIN 2008;139:90–105.