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Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α activated fibroblast-like synoviocytes: an in vitro, co-culture model of inflammatory pain

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Sampurna Chakrabarti, Zoe Hore, Luke A Pattison, Sylvine Lalnunhlimi, Charity N Bhebhe, Gerard Callejo, David C Bulmer, Leonie S Taams, Franziska Denk, Ewan St John Smith

Original languageEnglish
JournalPain
DOIs
E-pub ahead of print22 Apr 2020

King's Authors

Abstract

Pain is a principal contributor to the global burden of arthritis with peripheral sensitization being a major cause of arthritis-related pain. Within the knee joint, distal endings of dorsal root ganglion neurons (knee neurons) interact with fibroblast-like synoviocytes (FLS) and the inflammatory mediators they secrete, which are thought to promote peripheral sensitization. Correspondingly, RNA-sequencing has demonstrated detectable levels of pro-inflammatory genes in FLS derived from arthritic patients. This study confirms that stimulation with tumor necrosis factor (TNF-α), results in expression of pro-inflammatory genes in mouse and human FLS (derived from OA and RA patients), as well as increased secretion of cytokines from mouse TNF-α stimulated FLS (TNF-FLS). Electrophysiological recordings from retrograde labelled knee neurons co-cultured with TNF-FLS, or supernatant derived from TNF-FLS, revealed a depolarized resting membrane potential, increased spontaneous action potential firing and enhanced TRPV1 function, all consistent with a role for FLS in mediating the sensitization of pain-sensing nerves in arthritis. Therefore, data from this study demonstrate the ability of FLS activated by TNF-α to promote neuronal sensitization, results that highlight the importance of both non-neuronal and neuronal cells to the development of pain in arthritis.

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