The activation of proNGF/p75NTR pathway is a novel inflammatory mechanism in chronic arthritis

BACKGROUND: 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 increase in tissue and circulating NGF is a common feature of a variety of inflammatory diseases (Minnone et al. Int J Mol Sci. 2017). Chronic arthritis patients show a marked increase in p75NTR expression in synovial mononuclear cells (lymphocytes, monocytes) (Minnone et al., RMD Open, 2017) and in fibroblasts-like synoviocytes (Farina et al., Front Immunol., 2022). High proNGF concentrations characterize inflamed synovial fluids of chronic arthritis patients. In vitro, addition of proNGF leads, through activation of p75NTR, to downstream induction of inflammatory cytokine release in synovial mononuclear cells (Minnone et al., RMD Open, 2017) and in fibroblasts-like synoviocytes (Farina et al., Front Immunol., 2022).The Aims of the study were:To define how an active p75NTR pathway contributes to modulate inflammatory responses in juvenile Idiopathic arthritis (JIA) and rheumatoid arthritis (RA) patients. To investigate whether p75NTR expression could be used as a biomarker of disease activity and duration in JIA and RA patients. To verify the possibility of using p75NTR inhibitors to block inflammatory response in in vitro and in vivo models of rheumatoid arthritis. Our results indicated that Cluster of FLS, involved in joint inflammation and damage, show a distinctive overexpression of p75NTR in synovia of RA patients. In vitro RA-FLS maintain a high expression of p75NTR which is associated to a high production of proNGF, creating an autocrine loop that enhances RA-FLS production of inflammatory cytokines. In vivo experiments confirmed that an active proNGF/p75NTR axis drives inflammation in AIA synoviae as the treatment with LM11A-31 significantly ameliorates inflammatory symptoms. All together, our results suggest that the proNGF/p75NTR pathway could represent a novel target in the treatment of chronic arthritis.