NGF and its receptor system in the regulation of inflammatory response in Rheumatoid Arthritis

Nerve Growth Factor (NGF) is a key mediator in the cross-talk between the nervous and immune systems and plays a role in both neuronal cell function and immune cell activity. The distribution of NGF receptors in different areas of lymphoid organs suggests that basal NGF production not only regulates their innervation but can also exert an immunomodulatory activity. Immune cells are responsive to NGF and express the NGF receptors: TrkA, which seems to be relevant for the differentiation of immune cells, and p75NTR. The expression levels of TrkA and NGF are modulated by inflammatory mediators and the increase of NGF in the tissues and blood of patients correlates with the inflammatory state in many autoimmune and inflammatory diseases. We have demonstrated that NGF is part of a regulatory loop in monocytes, which are key players in the initiation and perpetuation of inflammation. Through the activation of TrkA signaling, NGF influences TLR ligand-activated pathways, causing a down-regulation of inflammatory cytokine production and up-regulation of anti-inflammatory mediators. Immune cells from arthritis patients are marked by a reduced expression of TrkA, suggesting that defective TrkA expression may facilitate pro-inflammatory mechanisms and contribute to chronic tissue inflammation and damage. While the expression of p75NTR has been described in immune cells, there is still little information on the effects of its pathway activation on inflammatory responses. In order to define the distinct roles of NGF receptors in chronic inflammation we investigated whether p75NTR and TrkA and their ligands, pro-NGF and NGF, modulate the activity of synovial fibroblasts and mononuclear cells in arthritis patients. Our results showed that blood and synovial mononuclear cells as well as synoviocytes of arthritis patients have an altered p75NTR/TrkA balance. p75NTR is expressed more in arthritis patients' cells while TrkA is the prevalent receptor in healthy donor cells. Analysis of the synovial fluid of arthritis patients showed that proNGF and not mature NGF is the prevalent NGF form in synovial fluids of patients with JIA and RA. Ex vivo experiments using arthritis patient cells showed that inflammatory stimuli induce proNGF release, which in turn activates inflammatory pathways, enhancing the production of pro-inflammatory cytokines. This effect is mediated by p75NTR since inhibition of proNGF binding to p75NTR, using LM11A-31, abolished the increase in pro-inflammatory cytokines induced by proNGF. The finding in arthritis patients that p75NTR expression is associated with disease severity and activity, as documented by the direct correlation with clinical parameters (i.e. active joints, CRP levels), suggests that activation of the p75NTR/proNGF axis may have a role in chronic inflammatory deseases. Our hypothesis is that abnormal p75NTR expression levels and the modified p75NTR/TrkA ratio observed in arthritis patients might have a crucial role in the chronicity of the inflammatory response, enhancing pro-inflammatory cytokine production and contributing to sustain local inflammation. In addition to p75NTR up-regulation, inflammatory stimuli increased the release of proNGF in synovial fluids of arthritis patients. The binding of proNGF to p75NTR induces a further increase in pro-inflammatory cytokine expression, creating a vicious circle that amplifies the inflammatory response. Blocking the binding of endogenous proNGF to p75NTR strongly reduces the production of inflammatory mediators. These findings on the role of an active proNGF/p75NTR axis in arthritis patients provide the rationale for the use of p75NTR inhibitors as a new therapeutic approach to chronic arthritis.