Nerve growth factor is regulated by toll-like receptor 2 in human intervertebral discs

Emerson Krock, J. Brooke Currie, Michael H. Weber, Jean A. Ouellet, Laura S. Stone, Derek H. Rosenzweig, Lisbet Haglund

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31 Scopus citations

Abstract

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-1β (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1β gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1β 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-κB, 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-κB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-κB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.

Original languageEnglish (US)
Pages (from-to)3541-3551
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number7
DOIs
StatePublished - Feb 12 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded by Canadian Institutes of Health Research (CIHR) Operating Grant CIHR MOP-119564 (to L. H., L. S. S., and J. A. O.) and a studentship from the McGill Faculty of Medicine and a Fonds de Recherche du Qu?bec-Sant? doctoral fellowship (to E. K.). The authors declare that they have no conflicts of interest with the contents of this article.

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