Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis

Barthel, Christian; Yeremenko, Nataliya; Jacobs, Roland; Schmidt, Reinhold; Bernateck, Michael; Zeidler, Henning; Tak, Paul‐Peter; Baeten, Dominique; Rihl, Markus

doi:10.1186/ar2716

Cited by 83 publications

(76 citation statements)

References 30 publications

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“…As previously mentioned, it is well known that chronic inflammatory diseases, such as JIA or rheumatoid arthritis, are characterized by high levels of NGF in the inflamed tissues (45)(46)(47). To evaluate whether these high levels of NGF exert their full inhibitory potential, we investigated the levels of TrkA expression in PBMC or SFMC of patients with JIA and compared them with agedmatched controls.…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Prencipe

Minnone

Strippoli

et al. 2014

The Journal of Immunology

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Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR responses. In TLR-activated monocytes, NGF reduces inflammatory cytokine production (IL-1β, TNF-α, IL-6, and IL-8) while inducing the release of anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist). NGF binding to TrkA affects TLR signaling, favoring pathways that mediate inhibition of inflammatory responses: it increases Akt phosphorylation, inhibits glycogen synthase kinase 3 activity, reduces IκB phosphorylation and p65 NF-κB translocation, and increases nuclear p50 NF-κB binding activity. Use of TrkA inhibitors in TLR-activated monocytes abolishes the effects of NGF on the activation of anti-inflammatory signaling pathways, thus increasing NF-κB pathway activation and inflammatory cytokine production while reducing IL-10 production. PBMC and mononuclear cells obtained from the synovial fluid of patients with juvenile idiopathic arthritis show marked downregulation of TrkA expression. In ex vivo experiments, the addition of NGF to LPS-activated juvenile idiopathic arthritis to both mononuclear cells from synovial fluid and PBMC fails to reduce the production of IL-6 that, in contrast, is observed in healthy donors. This suggests that defective TrkA expression may facilitate proinflammatory mechanisms, contributing to chronic tissue inflammation and damage. In conclusion, this study identifies a novel regulatory mechanism of inflammatory responses through NGF and its receptor TrkA, for which abnormality may have pathogenic implications for chronic inflammatory diseases

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Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Prencipe

Minnone

Strippoli

et al. 2014

The Journal of Immunology

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“…However, there is increasing evidence that NTs and NTRs are also expressed in nonneuronal tissues (1,3), and several recent works have elucidated a regulatory effect of NTs on the proinflammatory mediators, such as IL-1␤, TNF-␣, and IL-6 (3,14). In addition, BDNF and NGF are detectable and over-expressed in the synovial tissues and fluids of patients with rheumatoid arthritis (RA) and spondyloarthritis but not in healthy controls (15)(16)(17). Additional evidence exists for an association between increased levels of NTs and susceptibility to inflammatory diseases such as systemic lupus erythematosus (SLE) (18,19), RA, multiple sclerosis, and juvenile chronic arthritis (20 -22).…”

Section: Discussionmentioning

confidence: 99%

Linkage and Association Study of Neurotrophins and Their Receptors as Novel Susceptibility Genes for Childhood IgA Nephropathy

2011

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Neurotrophins (NTs) and their receptors (NTRs) are known to be important for pathogenesis of various inflammatory diseases that occur in not only neuronal but also nonneuronal tissues, including kidney. Here, we investigated association between childhood IgA nephropathy (IgAN) and single nucleotide polymorphisms (SNPs) of genes encoding NTs [nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] and NTRs [nerve growth factor receptor (NGFR) and neurotrophic tyrosine kinase receptor 1-3 (NTRK1-3)]. The genotyping data of 197 patients and 289 control subjects revealed significant association between NGF SNP rs11102930 and presence of IgAN. Patient subgroup analysis revealed that that the presence of nephrotic range proteinuria (Ͼ40 mg/m 2 /h) was associated with rs6334 of NTRK1 and rs11030104, rs7103411, rs7103873, and rs6484320 of BDNF. Significant genotype differences were observed in podocyte foot process effacement for rs1187321 and rs1187323 of NTRK2. Furthermore, some SNPs showed significantly different genotype distribution between patients with or without pathologically advanced disease markers, specifically in rs6334 of NTRK1. Our results suggest that SNPs of NTs and NTRs are associated with susceptibility, pathological advancement, podocyte foot process effacement, and development of proteinuria in childhood IgAN. (Pediatr Res 69: 299-305, 2011)

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“…Consequent therapies targeting neuronal transmission pathways are increasingly being thought to be useful for alleviating pain [6,7]. It is becoming clear, however, that neurotrophins such as NGF and brain-derived neurotrophic factor (BDNF) have a wide range of activities other than neurotransmission that include roles in tissue development, repair, modulation of inflammatory responses and bone and cartilage metabolism [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

et al. 2014

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Purpose Nerve growth factor (NGF) expression and activity is important in chronic lower back pain but may also act as a pro-catabolic factor in the pathogenesis of intervertebral disc (IVD) degeneration. Lipocalin 2 (Lcn2) expression in IVD was upregulated by NGF stimulation in our previous study. The current study was undertaken to identify potential mechanisms of the latter effect including potential interactions between Lcn2 and matrix metalloproteinase 9 (MMP9). Methods Rat annulus fibrosus (AF) cells were stimulated by NGF and subjected to microarray analysis, subsequent real-time PCR, western immunoblotting, and immunofluorescence. Cells were treated with NGF in the absence or presence of the NGF inhibitor Ro 08-2750. Zymography and functional MMP9 assays were used to determine MMP9 activity, whilst the dimethyl-methylene blue assay was used to quantify the release of glycosaminoglycans (GAGs) reflecting catabolic effects following NGF treatment. Immunoprecipitation with immunoblotting was used to identify interactions between MMP9 and Lcn2. Results Increased expression of Lcn2 gene and protein following NGF stimulation was confirmed by microarray analysis, real-time PCR, western blot and immunofluorescence. Zymography showed that NGF enhanced 125-kDa gelatinase activity, identified as a Lcn2/MMP9 complex by immunoprecipitation and immunoblotting. Functional assays showed increased MMP9 activity and GAG release in the presence of NGF. The effects of NGF were neutralized by the presence of Ro 08-2750. Conclusions NGF upregulates Lcn2 expression and increases MMP9 activity in AF cells; processes which are likely to potentiate degeneration of AF tissue in vivo. Anti-NGF treatment may have benefit for management of pain Electronic supplementary material The online version of this article

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Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis

Abstract: Introduction We previously described the presence of nerve growth factor receptors in the inflamed synovial compartment. Here we investigated the presence of the corresponding nerve growth factors, with special focus on nerve growth factor (NGF).

Cited by 83 publications

References 30 publications

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Linkage and Association Study of Neurotrophins and Their Receptors as Novel Susceptibility Genes for Childhood IgA Nephropathy

Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression

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