PMID:24585880

Citation	Prencipe, G, Minnone, G, Strippoli, R, De Pasquale, L, Petrini, S, Caiello, I, Manni, L, De Benedetti, F and Bracci-Laudiero, L' (2014) Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA. J. Immunol. '
Abstract	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.
Links	PubMed Online version:10.4049/jimmunol.1300825
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TLR2		GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000314:		P		TLR2 when stimulated with LTA increase expression of mRNA of Tyrosine receptor kinase A (TrkA) as shown in figure 3D and which is further translated to protein as shown in figure 3E.	complete CACAO 9647
HUMAN:TLR4		GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000314:		P		Figure 3 C stimulated with LPS show that when TLR4 is activated there is an increase of tyrosine receptor kinase A expression of mRNA (TrkA). This is further translated as indicated by the westerblot for TrkA in figure 3E.	complete CACAO 9646

References

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