{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:35:13Z","timestamp":1791387313794,"version":"4.3.3"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T00:00:00Z","timestamp":1712620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["UE171\/6-1"],"award-info":[{"award-number":["UE171\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["UE171\/15-1"],"award-info":[{"award-number":["UE171\/15-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["CRC1158"],"award-info":[{"award-number":["CRC1158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the \u03b1-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an <jats:italic>in vitro<\/jats:italic> model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate\/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, <jats:italic>KCNN4<\/jats:italic>) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.<\/jats:p>","DOI":"10.1371\/journal.pone.0300687","type":"journal-article","created":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T17:59:22Z","timestamp":1712685562000},"page":"e0300687","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Elevated interleukin-8 expression by skin fibroblasts as a potential contributor to pain in women with Fabry disease"],"prefix":"10.1371","volume":"19","author":[{"given":"Lukas","family":"Hofmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Gr\u00fcner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Klug","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Breyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Hochheimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Wagenh\u00e4user","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhard","family":"Wischmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-6428","authenticated-orcid":true,"given":"Nurcan","family":"\u00dc\u00e7eyler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,9]]},"reference":[{"key":"pone.0300687.ref001","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD((R))): optimizing its use in a clinical diagnostic or research setting.","volume":"139","author":"PD Stenson","year":"2020","journal-title":"Hum Genet"},{"key":"pone.0300687.ref002","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1016\/S0140-6736(09)61493-8","article-title":"Enzyme replacement therapy with agalsidase alfa in patients with Fabry\u2019s disease: an analysis of registry data","volume":"374","author":"A Mehta","year":"2009","journal-title":"Lancet"},{"key":"pone.0300687.ref003","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/S0140-6736(08)61589-5","article-title":"Fabry\u2019s disease.","volume":"372","author":"YA Zarate","year":"2008","journal-title":"Lancet"},{"key":"pone.0300687.ref004","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1097\/AJP.0000000000000041","article-title":"Characterization of pain in fabry disease","volume":"30","author":"N \u00dc\u00e7eyler","year":"2014","journal-title":"Clin J Pain"},{"key":"pone.0300687.ref005","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1136\/jmg.20.4.309","article-title":"Involvement of dorsal root ganglia in Fabry\u2019s disease","volume":"20","author":"N Gadoth","year":"1983","journal-title":"J Med Genet"},{"key":"pone.0300687.ref006","doi-asserted-by":"crossref","DOI":"10.1177\/1744806916663729","article-title":"Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model","volume":"12","author":"J Lakoma","year":"2016","journal-title":"Mol Pain"},{"key":"pone.0300687.ref007","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.39300","article-title":"Characterization of small fiber pathology in a mouse model of Fabry disease.","volume":"7","author":"L Hofmann","year":"2018","journal-title":"Elife"},{"key":"pone.0300687.ref008","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.99171","article-title":"Neuropathic pain in a Fabry disease rat model","volume":"3","author":"JJ Miller","year":"2018","journal-title":"JCI Insight"},{"key":"pone.0300687.ref009","doi-asserted-by":"crossref","first-page":"113134","DOI":"10.1016\/j.expneurol.2019.113134","article-title":"Globotriaosylceramide-induced reduction of KCa1.1 channel activity and activation of the Notch1 signaling pathway in skin fibroblasts of male Fabry patients with pain","volume":"324","author":"V Rickert","year":"2020","journal-title":"Exp Neurol"},{"key":"pone.0300687.ref010","doi-asserted-by":"crossref","first-page":"17529","DOI":"10.1074\/jbc.M113.499699","article-title":"Chemosensory information processing between keratinocytes and trigeminal neurons","volume":"289","author":"AC Sondersorg","year":"2014","journal-title":"J Biol Chem"},{"key":"pone.0300687.ref011","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.09674","article-title":"Keratinocytes can modulate and directly initiate nociceptive responses.","volume":"4","author":"KM Baumbauer","year":"2015","journal-title":"Elife"},{"key":"pone.0300687.ref012","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1111\/exd.13975","article-title":"Cutaneous nociception: Role of keratinocytes","volume":"28","author":"M Talagas","year":"2019","journal-title":"Exp Dermatol"},{"key":"pone.0300687.ref013","first-page":"2022.2002.2023.481592","article-title":"Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit.","author":"C Erbacher","year":"2022","journal-title":"bioRxiv"},{"key":"pone.0300687.ref014","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fphys.2017.00039","article-title":"Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by \u03b1-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C.","volume":"8","author":"A Oliv\u00e1n-Viguera","year":"2017","journal-title":"Front Physiol."},{"key":"pone.0300687.ref015","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1113\/jphysiol.1991.sp018568","article-title":"Characterization of ion channels seen in subconfluent human dermal fibroblasts","volume":"436","author":"M. Estacion","year":"1991","journal-title":"J Physiol"},{"key":"pone.0300687.ref016","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1038\/jid.2011.424","article-title":"Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea.","volume":"132","author":"M Sulk","year":"2012","journal-title":"J Invest Dermatol"},{"key":"pone.0300687.ref017","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1097\/j.pain.0000000000002122","article-title":"Differential impact of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in small fiber neuropathy","volume":"162","author":"L Kress","year":"2021","journal-title":"Pain"},{"key":"pone.0300687.ref018","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1097\/j.pain.0000000000001890","article-title":"Sensitization of knee-innervating sensory neurons by tumor necrosis factor-alpha-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain","volume":"161","author":"S Chakrabarti","year":"2020","journal-title":"Pain"},{"key":"pone.0300687.ref019","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.bbi.2023.06.011","article-title":"Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206(+) myeloid cells.","volume":"112","author":"R Garrity","year":"2023","journal-title":"Brain Behav Immun."},{"key":"pone.0300687.ref020","doi-asserted-by":"crossref","first-page":"e100235","DOI":"10.1136\/bmjos-2021-100235","article-title":"Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature","volume":"6","author":"N Shinotsuka","year":"2022","journal-title":"BMJ Open Sci."},{"key":"pone.0300687.ref021","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/j.1468-1331.2010.03023.x","article-title":"European Federation of Neurological Societies\/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society","volume":"17","author":"G Lauria","year":"2010","journal-title":"Eur J Neurol"},{"key":"pone.0300687.ref022","article-title":"Patient-derived in vitro skin models for investigation of small fiber pathology.","author":"F Karl","year":"2019","journal-title":"Ann Clin Transl Neurol."},{"key":"pone.0300687.ref023","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fcell.2019.00194","article-title":"Super-Resolution Microscopy Reveals Local Accumulation of Plasma Membrane Gangliosides at Neisseria meningitidis Invasion Sites","volume":"7","author":"J Schlegel","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"pone.0300687.ref024","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1006\/abio.1999.4085","article-title":"Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro","volume":"270","author":"J Winer","year":"1999","journal-title":"Anal Biochem"},{"key":"pone.0300687.ref025","first-page":"bioRxiv2023.2008.2009.552621","article-title":"Small fibre neuropathy in Fabry disease: a human-derived neuronal in vitro disease model.","author":"T Klein","year":"2023","journal-title":"BioRxiv"},{"key":"pone.0300687.ref026","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.stemcr.2015.07.010","article-title":"Pattern of Functional TTX-Resistant Sodium Channels Reveals a Developmental Stage of Human iPSC- and ESC-Derived Nociceptors","volume":"5","author":"E Eberhardt","year":"2015","journal-title":"Stem Cell Reports"},{"key":"pone.0300687.ref027","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF00656997","article-title":"Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches","volume":"391","author":"OP Hamill","year":"1981","journal-title":"Pflugers Arch"},{"key":"pone.0300687.ref028","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1186\/s12967-023-04475-y","article-title":"Proteomic analysis unveils Gb3-independent alterations and mitochondrial dysfunction in a gla(-\/-) zebrafish model of Fabry disease.","volume":"21","author":"HOA Elsaid","year":"2023","journal-title":"J Transl Med"},{"key":"pone.0300687.ref029","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1093\/hmg\/ddx032","article-title":"Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease","volume":"26","author":"JS Shen","year":"2017","journal-title":"Hum Mol Genet"},{"key":"pone.0300687.ref030","doi-asserted-by":"crossref","first-page":"36049","DOI":"10.1074\/jbc.M110.110189","article-title":"A major fraction of glycosphingolipids in model and cellular cholesterol-containing membranes is undetectable by their binding proteins","volume":"285","author":"R Mahfoud","year":"2010","journal-title":"J Biol Chem"},{"key":"pone.0300687.ref031","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/S1474-4422(14)70150-4","article-title":"Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use","volume":"13","author":"SG Waxman","year":"2014","journal-title":"Lancet Neurol"},{"key":"pone.0300687.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mcn.2015.02.001","article-title":"The importance of TRPV1-sensitisation factors for the development of neuropathic pain","volume":"65","author":"N Malek","year":"2015","journal-title":"Mol Cell Neurosci"},{"key":"pone.0300687.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2016.11.031","article-title":"Inhibition of the potassium channel K(Ca)3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury.","volume":"795","author":"RGW Staal","year":"2017","journal-title":"Eur J Pharmacol"},{"key":"pone.0300687.ref034","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1002\/jcp.24924","article-title":"Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients","volume":"230","author":"K Friebel","year":"2015","journal-title":"J Cell Physiol"},{"key":"pone.0300687.ref035","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.expneurol.2019.03.005","article-title":"Upregulation of interleukin-6 on Ca(v)3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation.","volume":"317","author":"Q Liu","year":"2019","journal-title":"Exp Neurol"},{"key":"pone.0300687.ref036","first-page":"662","article-title":"Human osteoarthritic synovial fluid increases excitability of mouse dorsal root ganglion sensory neurons: an in-vitro translational model to study arthritic pain","volume":"59","author":"S Chakrabarti","year":"2020","journal-title":"Rheumatology (Oxford)."},{"key":"pone.0300687.ref037","article-title":"Differential impact of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in small fiber neuropathy","author":"L Kre\u00df","year":"2020","journal-title":"Pain"},{"key":"pone.0300687.ref038","doi-asserted-by":"crossref","first-page":"5707","DOI":"10.1038\/s41598-017-05954-1","article-title":"Effect of CXCL12\/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion","volume":"7","author":"Y Yu","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0300687.ref039","doi-asserted-by":"crossref","first-page":"690858","DOI":"10.3389\/fnmol.2021.690858","article-title":"Oxaliplatin Depolarizes the IB4(-) Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice.","volume":"14","author":"B Wu","year":"2021","journal-title":"Front Mol Neurosci."},{"key":"pone.0300687.ref040","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.scr.2018.08.009","article-title":"Generation of the human induced pluripotent stem cell line (UKWNLi001-A) from skin fibroblasts of a woman with Fabry disease carrying the X-chromosomal heterozygous c.708 G > C (W236C) missense mutation in exon 5 of the alpha-galactosidase-A gene.","volume":"31","author":"T Klein","year":"2018","journal-title":"Stem Cell Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0300687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,9]],"date-time":"2024-04-09T17:59:57Z","timestamp":1712685597000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0300687"}},"subtitle":[],"editor":[{"given":"Israel","family":"Silman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,4,9]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0300687","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,9]]}}}