Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells

Klawitter, Marina; Hakozaki, Michiyuki; Kobayashi, Hiroshi; Krupková, Olga; Quero, Lilian; Ospelt, Caroline; Gay, Steffen; Hausmann, Oliver; Liebscher, Thomas; Meier, Ullrich; Sekiguchi, Miho; Konno, Satoshi; Boos, Norbert; Ferguson, Stephen J.; Wuertz, Karin

doi:10.1007/s00586-014-3442-4

Cited by 73 publications

(95 citation statements)

References 55 publications

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“…Toll-like Receptor Expression-Increased TLR1, -2, -4, and -6 gene expression has been correlated with an increasing degree of degeneration (11). TLR2 can signal as a homodimer or heterodimer with TLR1 or TLR6, whereas TLR4 signals primarily as a homodimer (10).…”

Section: Resultsmentioning

confidence: 99%

“…A current hypothesis is that ECM-produced alarmins, potentially generated by mechanical trauma, activate TLR signaling in early stages of disc degeneration (11,12,35). TLR activation can result in a robust increase of inflammatory cytokines and catabolic proteases, which in turn can further drive degeneration.…”

Section: Tlr2 Regulates Ngf Via Nf-bmentioning

confidence: 99%

“…Protease activity degrades the extracellular matrix (ECM), and the generated ECM fragments can potentially function as endogenous danger-associated patterns (DAMPs) also known as "alarmins" (10). Alarmins have been shown to activate toll-like receptors (TLRs) in other tissues, resulting in a robust increase of inflammatory cytokines including IL-1␤ and TNF␣ (11,12). TLRs have recently been proposed to contribute to disc degeneration, and their activation may play an important role in the induction of inflammatory cytokines and pain mediators implicated in painful disc degeneration.…”

mentioning

confidence: 99%

“…In humans, 10 TLRs have been described. Gene expression of TLRs 1, 2, 3, 4, 5, 6, 9, and 10 have been detected in human disc cells where expression of TLRs 1, 2, 4, and 6 are correlated with an increasing degree of degeneration (11). Alarmins include proteolysisgenerated ECM fragments, such as fragmented hyaluronic acid, fibronectin, biglycan, tenacin C, versican, heparan sulfate, and aggrecan and high mobility group B1 and the heat shock proteins 60 and 70 (10,30,31).…”

mentioning

confidence: 99%

“…TLR2 and TLR4 are thought to be the primary TLR subtypes that recognize ECM alarmins, where TLR4 functions as a homodimer and TLR2 functions as a homodimer or heterodimer with TLR1 or -6 (10). TLR activation increases the catabolic proteases matrix metalloproteinase-1 and -13 as well as IL-1␤, IL-6, and IL-8 in disc cells (11,36). Interestingly, in vivo injection of fibronectin fragments into rabbit discs induces degenerative changes (37), and exposure of NP cells to fibronectin fragments decreases proteoglycan synthesis and increases proteoglycan degradation (38).…”

mentioning

confidence: 99%

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Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1␤ (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1␤ gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1␤ treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-B, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-B signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-B inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Tlr2 Regulates Ngf Via Nf-bmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Krock

Currie

Weber

et al. 2016

Journal of Biological Chemistry

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Exploring the Impact of TLR‐2 Signaling on miRNA Dysregulation in Intervertebral Disc Degeneration

Cazzanelli,

Lamoca,

Hausmann

et al. 2024

Advanced Biology

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Toll‐like receptors (TLRs) are key mediators of inflammation in intervertebral disc (IVD) degeneration. TLR‐2 activation contributes to the degenerative process by increasing the expression of extracellular matrix‐degrading enzymes, pro‐inflammatory cytokines, and neurotrophins. As potent post‐transcriptional regulators, microRNAs can modulate intracellular mechanisms, and their dysregulation is known to contribute to numerous pathologies. This study aims to investigate the impact of TLR‐2 signaling on miRNA dysregulation in the context of IVD degeneration. Small‐RNA sequencing of degenerated IVD cells shows the dysregulation of ten miRNAs following TLR‐2 activation by PAM2CSK4. The miR‐155‐5p is most significantly upregulated in degenerated and non‐degenerated annulus fibrosus and nucleus pulposus cells. Sequence‐based target and pathway prediction shows the involvement of miR‐155‐5p in inflammation‐ and cell fate‐related pathways and TLR‐2‐induced miR‐155‐5p expression leads to the downregulation of its target c‐FOS. Furthermore, changes specific to the activation of TLR‐2 through fragmented fibronectin are seen in miR‐484 and miR‐487. Lastly, miR‐100‐3p, miR‐320b, and miR‐181a‐3p expression exhibit degeneration‐dependent changes. These results show that TLR‐2 signaling leads to the dysregulation of miRNAs in IVD cells as well as their possible downstream effects on inflammation and degeneration. The identified miRNAs provide important opportunities as potential therapeutic targets for IVD degeneration and low back pain.

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MicroRNA‐223 inhibits lipopolysaccharide‐induced inflammatory response by directly targeting Irak1 in the nucleus pulposus cells of intervertebral disc

et al. 2018

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This study was aimed to research the effect of miR-223 on the inflammatory responses induced by lipopolysaccharide (LPS) in nucleus pulposus (NP) cells of rat intervertebral disc. Isolated rat NP cells were induced by LPS. Reverse transcriptase quantitative real-time polymerase chain reaction was used to detect gene expression. To detect protein expression, Western blot and enzyme-linked immunosorbent assay experiments were applied. The putative targeting relationship between miR-223 and Irak1 was determined using dual-luciferase reporter gene assay. We found that miR-223 was downregulated in LPS-induced NP cells. MiR-223 upregulated the expression of extracellular matrix-related genes (Aggrecan and Collagen II). Matrix degrading enzymes (ADAMTS4, ADAMTS5, MMP3 and MMP13), NO reaction-associated proteins (PGE2, COX-2 and INOS) and the expression of nuclear factor (NF)-κB signaling-related proteins were downregulated after miR-233 overexpression. In addition, luciferase reporter assays demonstrated that miR-223 directly targeted Irak1. MiR-223 overexpression could inhibit NF-κB signaling by targeting Irak1, and finally suppress the LPS-induced inflammation in NP cells. © 2018 IUBMB Life, 70(6):479-490, 2018.

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Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells

Cited by 73 publications

References 55 publications

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

Exploring the Impact of TLR‐2 Signaling on miRNA Dysregulation in Intervertebral Disc Degeneration

MicroRNA‐223 inhibits lipopolysaccharide‐induced inflammatory response by directly targeting Irak1 in the nucleus pulposus cells of intervertebral disc

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