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Sensitization of knee-innervating sensory neurons by tumor necrosis factor-?-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain.

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 proinflammatory genes in FLS derived from arthritis patients. This study confirms that stimulation with tumor necrosis factor (TNF-?) results in expression of proinflammatory genes in mouse and human FLS (derived from osteoarthritis and rheumatoid arthritis patients), as well as increased secretion of cytokines from mouse TNF-?-stimulated FLS (TNF-FLS). Electrophysiological recordings from retrograde labelled knee neurons cocultured 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-? to promote neuronal sensitization, results that highlight the importance of both nonneuronal and neuronal cells to the development of pain in arthritis.

SUBMITTER: Chakrabarti S

PROVIDER: S-EPMC7431145 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Chakrabarti Sampurna S Hore Zoe Z Pattison Luke A LA Lalnunhlimi Sylvine S Bhebhe Charity N CN Callejo Gerard G Bulmer David C DC Taams Leonie S LS Denk Franziska F Smith Ewan St John ESJ

Pain 20200901 9

<h4>Abstract</h4>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 proinflammatory genes in FLS derived ...[more]

PMID: 32332252

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Project description:High mobility group box 1 (HMGB1) is an important downstream product of pyroptosis in macrophages, and it serves a vital role in numerous inflammatory diseases. Previous studies have reported that HMGB1 is released by fibroblast?like synoviocytes (FLSs) that are activated by inflammatory cytokines in knee osteoarthritis (KOA); however, the mechanism via which FLS promotes HMGB1 secretion in KOA remains unknown. According to our previous study, pyroptosis occurs in FLSs of patients with KOA and is mediated by Nod?like receptor protein (NLRP)1 or NLRP3 inflammasomes. However, the specific relationship between HMGB1 secretion and FLS pyroptosis requires further investigation. In the present study, the association between HMGB1 secretion and FLS pyroptosis was investigated in vitro and in vivo. In this study, western blotting, ELISA and reverse transcription?quantitative PCR were used to measure expression levels of proteins and mRNA. Caspase?1 activity assay and Hoechst 33342/PI double staining were used to observe the pyroptosis of FLSs. Hematoxylin and eosin staining was used to observe the destruction of cartilage in KOA. Increased expression levels of pyroptosis?related proteins and HMGB1 in the synovium of rat anterior cruciate ligament transection?induced KOA models were identified, and these changes were significantly mitigated via the intra?articular injection of a caspase?1 inhibitor. In vitro, FLSs were treated with lipopolysaccharide (LPS) + ATP to induce pyroptosis, and HMGB1 secretion was subsequently measured. LPS + ATP significantly increased the expression levels of pyroptosis?related proteins and HMGB1 in FLSs, and these effects were significantly mitigated by small interfering RNAs targeting NLRP1, NLRP3, apoptosis?associated speck?like protein with a caspase?recruitment domain or caspase?1. Therefore, the present results indicated that NLRP1/NLRP3 inflammasome?mediated and caspase?1?dependent FLS pyroptosis increased HMGB1 secretion in KOA. These findings may provide a therapeutic strategy to decrease synovial inflammatory responses during KOA progression.

Dataset Information

Sensitization of knee-innervating sensory neurons by tumor necrosis factor-?-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain.

Publications

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

Similar Datasets

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