title: Nerve growth factor downregulates inflammatory response in human monocytes through TrkA.
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.
authors.affiliation: Research Laboratories, Unit of Rheumatology, Bambino Gesù Children's Hospital, 00165 Rome, Italy;
authors.forename: Giusi
authors.initials: G
authors.lastname: Prencipe
authors.forename: Gaetana
authors.initials: G
authors.lastname: Minnone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Strippoli
authors.forename: Loredana
authors.initials: L
authors.lastname: De Pasquale
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrini
authors.forename: Ivan
authors.initials: I
authors.lastname: Caiello
authors.forename: Luigi
authors.initials: L
authors.lastname: Manni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci-Laudiero
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020932:Nerve Growth Factor / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D020917:Receptor, trkA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051193:Toll-Like Receptors; D016753:Interleukin-10; D020932:Nerve Growth Factor; D020917:Receptor, trkA