RT Journal Article
SR Electronic
T1 ProNGF-p75NTR axis plays a proinflammatory role in inflamed joints: a novel pathogenic mechanism in chronic arthritis
JF RMD Open
JO RMD Open
FD EULAR
SP e000441
DO 10.1136/rmdopen-2017-000441
VO 3
IS 2
A1 Gaetana Minnone
A1 Marzia Soligo
A1 Ivan Caiello
A1 Giusi Prencipe
A1 Luigi Manni
A1 Denise Pires Marafon
A1 Silvia Magni-Manzoni
A1 Antonio Manzo
A1 Fabrizio De Benedetti
A1 Luisa Bracci-Laudiero
YR 2017
UL http://rmdopen.bmj.com/content/3/2/e000441.abstract
AB Objective To identify the role of mature nerve growth factor (mNGF), its immature form proNGF and their receptors in arthritis inflammation.Methods Real-time PCR, western blot and ELISA were performed to evaluate NGF, proNGF, their receptor and cytokine expression in synovial tissue and cells of patients with juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA), and controls.Results proNGF and not mNGF is the prevalent form measured in synovial fluids of patients with JIA and RA with synovial fibroblasts as a major source of proNGF in the inflamed synoviae. p75NTR, the specific receptor for proNGF, is the NGF receptor most expressed in mononuclear cells of patients with JIA, while TrkA is the prevalent receptor in healthy donors. In ex vivo experiments the effects of proNGF differ from those of mNGF, suggesting that the balance of p75NTR and TrkA expression represents a critical factor in regulating mNGF/proNGF functions, determining which intracellular pathways and biological activities are triggered. Contrary to NGF, proNGF administration increased inflammatory cytokines but not interleukin (IL)-10 expression, inducing a stronger activation of p38 and JNK pathways. proNGF effects depend on its binding to p75NTR, as inhibition of p75NTR with neutralising antibodies or LM11A-31 abolished proNGF-induced production of IL-6 in patients’ mononuclear cells, while inhibition of TrkA did not. There is a correlation in patients with arthritis between high p75NTR levels and severity of clinical symptoms.Conclusions Our data suggest that an active proNGF-p75NTR axis promotes proinflammatory mechanisms contributing to chronic tissue inflammation, and that the use of p75NTR inhibitors may represent a new therapeutic approach in chronic arthritis.